Prodrug substituted polycyclic carbamoyl pyridone derivative

ABSTRACT

The present invention provides a compound having antiviral effects, particularly having growth inhibitory activity on influenza viruses, a preferred example of the compound being a substituted 3-hydroxy-4-pyridone derivative prodrug having cap-dependent endonuclease inhibitory activity.

TECHNICAL FIELD

This invention relates to substituted polycyclic carbamoylpyridonederivatives having cap-dependent endonuclease inhibitory activity,prodrugs thereof, and pharmaceutical compositions including thereof.

BACKGROUND ART

Influenza is an acute respiratory infectious disease caused by infectionwith an influenza virus. In Japan, there is a report of millions ofinfluenza-like patients every winter, and influenza is accompanied withhigh morbidity and mortality. Influenza is a particularly importantdisease in a high risk population such as baby and elderly, acomplication rate with pneumonia is high in elderly, and death withinfluenza is occupied with elderly in many cases.

As anti-influenza drugs, Symmetrel (trade name: Amantadine) andFlumadine (trade name: Rimantadine) which inhibit the denucleationprocess of a virus, and Oseltamivir (trade name: Tamiflu) and Zanamivir(trade name: Relenza) which are neuraminidase inhibitors suppressingvirus budding and release from a cell are known. However, since problemsof appearances of resistant strains and side effects, and worldwideepidemic of a new-type influenza virus having high pathogenicity andmortality are feared, development of an anti-influenza drug having anovel mechanism has been desired.

Since a cap-dependent endonuclease which is an influenza virus-derivedenzyme is essential for virus proliferation, and has the virus-specificenzymatic activity which is not possessed by a host, it is believed thatthe endonuclease is suitable for a target of an anti-influenza drug. Thecap-dependent endonuclease has a host mRNA precursor as a substrate, andhas the endonuclease activity of producing a fragment of 9 to 13 basesincluding a cap structure (not including the number of bases of the capstructure). This fragment functions as a primer of a virus RNApolymerase, and is used in synthesizing mRNA encoding a virus protein.That is, it is believed that a substance which inhibits thecap-dependent endonuclease inhibits synthesis of a virus protein byinhibiting synthesis of virus mRNA and, as a result, inhibits virusproliferation.

As the substance which inhibits the cap-dependent endonuclease,flutimide (Patent Document 1 and Non-Patent Documents 1 and 2) and4-substituted 2,4-dioxobutanoic acid (Non-Patent Documents 3 to 5) andthe like have been reported, but they have not yet led to clinical useas anti-influenza drugs. In addition, Patent Documents 2 to 16 andNon-Patent Document 6 describe compounds having a similar structure tothat of this invention as a compound having integrase inhibitoryactivity, however, the documents do not describe cap-dependentendonuclease. In addition, Patent Document 17 describes an inventionrelating to “substituted polycyclic carbamoylpyridone derivative” havingcap-dependent endonuclease inhibitory activity, that has been filed bythe applicants, but does not describe the prodrug relating to thepresent invention.

PRIOR ART DOCUMENTS Patent Documents

-   [Patent Document 1] GB No. 2280435 specification-   [Patent Document 2] International Publication No. 2007/049675    pamphlet-   [Patent Document 3] International Publication No. 2006/088173    pamphlet-   [Patent Document 4] International Publication No. 2006/066414    pamphlet-   [Patent Document 5] International Publication No. 2005/092099    pamphlet-   [Patent Document 6] International Publication No. 2005/087766    pamphlet-   [Patent Document 7] International Publication No. 2005/016927    pamphlet-   [Patent Document 8] International Publication No. 2004/024078    pamphlet-   [Patent Document 9] International Publication No. 2006/116764    pamphlet-   [Patent Document 10] International Publication No. 2010/011818    pamphlet-   [Patent Document 11] International Publication No. 2010/011816    pamphlet-   [Patent Document 12] International Publication No. 2010/011819    pamphlet-   [Patent Document 13] International Publication No. 2010/011815    pamphlet-   [Patent Document 14] International Publication No. 2010/011814    pamphlet-   [Patent Document 15] International Publication No. 2010/011812    pamphlet-   [Patent Document 16] International Publication No. 2011/011483    pamphlet-   [Patent Document 17] International Publication No. 2010/147068    pamphlet

Non-Patent Documents

-   [NON-PATENT DOCUMENT 1] Tetrahedron Lett 1995, 36 (12), 2005-   [NON-PATENT DOCUMENT 2] Tetrahedron Lett 1995, 36 (12), 2009-   [NON-PATENT DOCUMENT 3] Antimicrobial Agents And Chemotherapy,    December 1994, p. 2827-2837-   [NON-PATENT DOCUMENT 4] Antimicrobial Agents And Chemotherapy, May    1996, p. 1304-1307-   [NON-PATENT DOCUMENT 5] J. Med. Chem. 2003, 46, 1153-1164-   [NON-PATENT DOCUMENT 6] Bioorganic & Medicinal Chemistry Letters    17 (2007) 5595-5599

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide compounds havingantiviral activities, especially inhibiting growth activity of influenzavirus. Another object of the present invention is to provide compoundsbeing efficiently absorbed into the body after administration andshowing high pharmacological effect by converting into a prodrug acompound used for in vivo administration (for example, oraladministration). More preferably, this invention provides compounds andmedicament containing the same which inhibit increase of influenza virusby exhibiting cap-dependent endonuclease inhibitory activity after invivo administration.

Means for Solving the Problems

The present invention provides inventions shown below.

(Item 1)

A compound represented by formula (I):

a pharmaceutically acceptable salt, or a solvate thereof:

(wherein

P^(R) is a group to form a prodrug (preferably, except for a benzylgroup and methoxy group);

R^(1a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,

—Z—N(R^(A1))(R^(A2)),

—Z—N(R^(A3))—SO₂—(R^(A4)),

—Z—C(═O)—N(R^(A5))—SO₂—(R^(A6)),

—Z—N(R^(A7))—C(═O)—R^(A7),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),

—Z—S(═O)—R¹¹,

—Z—N(R^(A12))—C(═O)—O—R^(A13),

—Z—N(R^(A14))—C(═O)—N(R^(A15))(R^(A16))

—Z—C(═O)—N(R^(A17))—C(═O)—N(R^(A18))(R^(A19)),

—Z—N(R^(A20))—C(═O)—C(═O)—R²¹, or

—Z—B(—OR^(A22))(—OR^(A23))

(wherein R^(A1), R^(A2), R^(A3), R^(A5), R^(A7), R^(A8), R^(A9),R^(A12), R^(A13), R^(A14), R^(A15), R^(A16), R^(A17), R^(A18), R^(A19),R^(A20) and R^(A21) are each independently selected from a substituentgroup consisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,

R^(A4), R^(A6), R^(A10), and R^(A11) are each independently selectedfrom a substituent group consisting of lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C,

R^(A1) and R^(A2), R^(A15) and R^(A16), and R^(A18) and R^(A19), eachmay be taken together with an adjacent atom to form heterocycle,

R^(A22) and R^(A23) are each independently an hydrogen atom, lower alkyloptionally substituted by substituent group C, or R^(A22) and R^(A23)may be taken together with an adjacent atom to form heterocycle, and

Z is a single bond or straight or branched lower alkylene);

R^(2a) is hydrogen, halogen, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkynyl optionally substitutedby substituent group C, lower alkyloxy optionally substituted bysubstituent group C, lower alkenyloxy optionally substituted bysubstituent group C, lower alkylcarbonyl optionally substituted bysubstituent group C, lower alkyloxycarbonyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocyclecarbonyl optionally substituted bysubstituent group C, carbocycleoxy optionally substituted by substituentgroup C, carbocycleoxycarbonyl optionally substituted by substituentgroup C, heterocyclic group optionally substituted by substituent groupC, heterocycle lower alkyl optionally substituted by substituent groupC, heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Z—N(R^(B1))—SO₂—R^(B2),

—Z—N(R^(B3))—C(═O)—R^(B4),

—Z—N(R^(B5))—C(═O)—O—R^(B6),

—Z—C(═O)—N(R^(B7))(R^(B8)),

—Z—N(R^(B9))(R^(B10)), or

—Z—SO₂—R^(B11)

(wherein R^(B1), R^(B3), R^(B4), R^(B5), R^(B6), R^(B7), R^(B8), R^(B9),and R^(B10) are each independently selected from a substituent groupconsisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,

R^(B2) and R^(B11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,

R^(B7) and R^(B8), and R^(B9) and R^(B10) may be taken together with anadjacent atom to form heterocycle and

Z is a single bond or straight or branched lower alkylene);

R^(3a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy lower alkyl optionally substitutedby substituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,

—Z—N(R^(C1))—SO₂—R^(C2),

—Z—N(R^(C3))—C(═O)—R^(C4),

—Z—N(R^(C5))—C(═O)—O—R^(C6),

—Z—C(═O)—N(R^(C7))(R^(C8)),

—Z—N(R^(C9))(R^(C10)),

—Z—SO₂—R^(C11), or

—Z—N(R^(C12))—O—C(═O)—R^(C13)

(wherein R^(C1), R^(C3), R^(C4), R^(C5), R^(C6), R^(C7), R^(C8), R^(C9),R^(C10), R^(C12), and R^(C13) are each independently selected from asubstituent group consisting of hydrogen, lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C,

R^(C2) and R^(C11) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,

R^(C7) and R^(C8), and R^(C9) and R^(C10) each may be taken togetherwith an adjacent atom to form heterocycle, and

Z is a single bond or straight or branched lower alkylene) and;

a) either B¹ or B² is CR^(5a)R^(6a), and the other is NR^(7a), or

b) B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),

R^(5a), R^(6a), R^(7a), R^(8a), R^(9a), R^(10a), and R^(11a) are eachindependently selected from a substituent group consisting of hydrogen,carboxy, cyano, lower alkyl optionally substituted by substituent groupC, lower alkenyl optionally substituted by substituent group C, loweralkynyl optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, carbocycle loweralkyl optionally substituted by substituent group C, carbocycleoxy loweralkyl optionally substituted by substituent group C, carbocyclecarbonyloptionally substituted by substituent group C, carbocycleoxycarbonyloptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, heterocycle lower alkyloptionally substituted by substituent group C, heterocycleoxy loweralkyl optionally substituted by substituent group C, heterocyclecarbonyloptionally substituted by substituent group C, heterocycleoxycarbonyloptionally substituted by substituent group C,

—Y—S—R^(D1),

—Z—S(═O)—R^(D2),

—Z—SO₂—R^(D3),

—C(═O)—C(═O)—R^(D4),

—C(═O)—N(R^(D5))(R^(D6)),

—Z—C(R^(D7))(R^(D8))(R^(D9)),

—Z—CH₂—R^(D10),

—Z—N(R^(D1))—C(═O)—O—R^(D12), or

—Z—N(R^(D13))—C(═O)—R^(D14), or

R^(5a) and R^(6a) may be taken together to form heterocyclic groupoptionally substituted by substituent group C

(wherein R^(D1), R^(D4), R^(D5), R^(D6), R^(D9), RD¹¹, R^(D12), R^(D13),and R^(D14) are each independently selected from a substituent groupconsisting of hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC,

R^(D2) and R^(D3) are each independently selected from a substituentgroup consisting of lower alkyl optionally substituted by substituentgroup C, lower alkenyl optionally substituted by substituent group C,lower alkynyl optionally substituted by substituent group C, carbocyclicgroup optionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, and heterocycle loweralkyl optionally substituted by substituent group C,

R^(D7), R^(D8), and R^(D10) are each independently carbocyclic groupoptionally substituted by substituent group C, or heterocyclic groupoptionally substituted by substituent group C,

R^(D5) and R^(D6) may be taken together with an adjacent atom to formheterocycle,

Y is straight or branched lower alkylene, and

Z is a single bond or straight or branched lower alkylene), and

R^(D5) and R^(D6) may be taken together with an adjacent atom to formcarbocycle;

1) when B¹ is CR^(5a)R^(6a) and B² is NR^(7a),

R^(3a) and R^(7a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D,

2) when B is NR^(7a) and B² is CR^(5a)R^(6a),

R^(3a) and R^(6a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, or

3) when B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),

R^(8a) and R^(10a) may be taken together with an adjacent atom to formcarbocycle or heterocycle optionally substituted by substituent group D,or

R^(3a) and R^(11a) may be taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D;

wherein

when B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a), and R^(9a) ishydrogen, and R^(11a) is hydrogen,

i) either R^(8a) or R^(10a) is

—Z—C(R^(E1))(R^(E2))(R^(E3)),

—Y—S—R^(E4),

—Z—CH₂—R^(E5), or

a group shown below:

(wherein R^(E1) and R^(E2) are each independently, selected from asubstituent group consisting of carbocyclic group optionally substitutedby substituent group C, and heterocyclic group optionally substituted bysubstituent group C,

R^(E3) is selected from a substituent group consisting of hydrogen,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, and heterocycle lower alkyloptionally substituted by substituent group C,

R^(E4) is selected from a substituent group consisting of carbocyclelower alkyl optionally substituted by substituent group C, andheterocycle lower alkyl optionally substituted by substituent group C,

R^(E5) is aromatic heterocyclic group optionally substituted bysubstituent group C,

R^(E6) is selected from a substituent group C,

m is an integer of 0 or 1 or more, provided that

m of R^(E6)s is same or different groups selected from substituent groupC,

Y is straight or branched lower alkylene, and

Z is a single bond or straight or branched lower alkylene); and

ii) the other of R⁸ or R^(10a) is

hydrogen, carboxy, cyano, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,lower alkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,carbocyclecarbonyl optionally substituted by substituent group C,carbocycleoxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC, heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Y—S—R^(F1),

—C(═O)—C(═O)—R^(F2), or

—C(═O)—N(R^(F3))(R^(F4))

(wherein R^(F1), R^(F2), R^(F3), and R^(F4) are each independentlyselected from a substituent group consisting of hydrogen, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkynyl optionally substitutedby substituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C, and

Y is straight or branched lower alkylene);

with a proviso that the following c) and d) are excluded

c) R^(5a), R^(6a), and R^(7a) are all hydrogens.

d) R^(8a), R^(9a), R^(10a), and R^(11a) are all hydrogens;

Substituent group C: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, lower alkenyl, lower alkynyl, halogeno loweralkyl, lower alkyloxy, lower alkynyloxy, lower alkylthio, hydroxy loweralkyl, carbocyclic group, heterocyclic group, heterocyclic groupsubstituted by oxo, carbocycle lower alkyloxy, carbocycleoxy loweralkyl, carbocycle lower alkyloxy lower alkyl, heterocycle loweralkyloxy, heterocycleoxy lower alkyl, heterocycle lower alkyloxy loweralkyl, halogeno lower alkyloxy, lower alkyloxy lower alkyl, loweralkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkylcarbonyloxy,lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino,halogeno lower alkyl carbonylamino, lower alkylaminocarbonyl, loweralkylsulfonyl, lower alkylsulfinyl, and lower alkylsulfonylamino;

Substituent group D: halogen, cyano, hydroxy, carboxy, formyl, amino,oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy,carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno loweralkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy,lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, loweralkylsulfonylamino, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, and heterocycle lower alkyl optionally substitutedby substituent group C).

(Item 2)

The compound according to item 1, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, cyano, formyl,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,

—Z—N(R^(A1))(R^(A2)),

—Z—N(R^(A3))—SO₂—(R^(A4)),

—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),

—Z—N(R^(A12))—C(═O)—O—R^(A13),

—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21),or

—Z—B(—OR^(A22))(—OR^(A23))

substituent group C, R^(A1), R^(A2), R^(A3), R^(A4), R^(A7), R^(A8),R^(A9), R^(A10), R^(A12), R^(A13), R^(A20), R^(A21), R^(A22), R^(A23),and Z are same as those of item 1).

(Item 3)

The compound according to item 1, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C,

—Z—N(R^(A1))(R^(A2)),

—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—N(R^(A12))—C(═O)—O—R^(A13), or

—Z—B(—OR^(A22))(—OR^(A23))

(substituent group C, R^(A1), R^(A2), R^(A7), R^(A8), R^(A12), R^(A13),R^(A22), R^(A23), and Z are same as those of item 1).

(Item 4)

The compound according to item 1, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, or

—Z—N(R^(A1))(R^(A2))

(substituent group C, R^(A1), R^(A2), and Z are same as those of item1).

(Item 5)

The compound according to item 1, or the pharmaceutically acceptablesalt thereof or the solvate thereof, wherein R^(1a) is hydrogen, orcarboxy.

(Item 6)

The compound according to any one of items 1 to 5, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(2a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, or

—Z—N(R^(B9))(R^(B10))

(substituent group C, R^(B9), R^(B10), and Z are same as those of item1).

(Item 7)

The compound according to any one of items 1 to 5, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(2a) is hydrogen or lower alkyl optionally substituted bysubstituent group C

(substituent group C is same as that of item 1).

(Item 8)

The compound according to any one of items 1 to 7, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(3a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,

—Z—N(R^(C1))—SO₂—R^(C2),

—Z—N(R^(C3))—C(═O)—R^(C4),

—Z—N(R^(C5))—C(═O)—O—R^(C6),

—Z—C(═O)—N(R^(C7))(R^(C8)), or

—Z—N(R^(C9))(R^(C10))

(substituent group C, R^(C1), R^(C2), R^(C3), R^(C4), R^(C5), R^(C6),R^(C7), R^(C8), R^(C9), R^(C10), and Z are same as those of item 1).

(Item 9)

The compound according to any one of items 1 to 7, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein R^(3a) is hydrogen, lower alkyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C,

(substituent group C is same as that of item 1).

(Item 10)

The compound according to any one of items 1 to 9, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is NR^(7a), and B² is CR^(5a)R^(6a), and

R^(5a), R^(6a) and R^(7a) are each independently hydrogen, carboxy,cyano, lower alkyl optionally substituted by substituent group C, loweralkenyl optionally substituted by substituent group C, lower alkynyloptionally substituted by substituent group C, lower alkyl carbonyloptionally substituted by substituent group C, lower alkyl oxycarbonyloptionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, carbocycle lower alkyloptionally substituted by substituent group C, carbocycleoxy lower alkyloptionally substituted by substituent group C, carbocyclecarbonyloptionally substituted by substituent group C, carbocycleoxycarbonyloptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, heterocycle lower alkyloptionally substituted by substituent group C, heterocycleoxy loweralkyl optionally substituted by substituent group C, heterocyclecarbonyloptionally substituted by substituent group C, heterocycleoxycarbonyloptionally substituted by substituent group C,

—Y—S—R^(D1),

—Z—S(═O)—R^(D2),

—Z—SO₂—R^(D3),

—C(═O)—C(═O)—R^(D4),

—C(═O)—N(R^(D5))(R^(D6)),

—Z—C(R^(D7))(R^(D8))(R^(D9)),

—Z—N(R^(D11))—C(═O)—O—R^(D12), or

—Z—N(R^(D13))—C(═O)—R^(D14)

substituent group C R^(D1), R^(D2), R^(D3), R^(D4), R^(D5), R^(D6),R^(D7), R^(D8), R^(D9), R^(D11), R^(D12), R^(D13), R^(D14), Y, and Z aresame as those of item 1).

(Item 11)

The compound according to any one of items 1 to 9, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is NR^(7a), and B² is CR^(5a)R^(6a),

R^(5a) is hydrogen,

R^(6a) is hydrogen, or lower alkyl optionally substituted by substituentgroup C, and

R^(7a) is lower alkyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,or

—Z—C(R^(D7))(R^(D8))(R^(D9))

(substituent group C, R^(D7), R^(D8), R^(D9), and Z are same as those ofitem 1).

(Item 12)

The compound according to any one of items 1 to 9, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(5a)R^(6a), and B² is NR^(7a),

R^(5a) is hydrogen,

R^(6a) is hydrogen, or lower alkyl optionally substituted by substituentgroup C, and

R^(7a) is lower alkyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,or

—Z—C(R^(D7))(R^(D8))(R^(D9))

(substituent group C, R^(D7), R^(D8), R^(D9), and Z are same as those ofitem 1).

(Item 13)

The compound according to items 11 or 12, or the pharmaceuticallyacceptable salt thereof or the solvate thereof,

wherein R^(7a) is a group shown below:

(wherein R^(E6) and m are same as those of item 1).

(Item 14)

The compound according to item 1, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(1a) is hydrogen, or carboxy,

R^(2a) is hydrogen,

R^(3a) is lower alkyl optionally substituted by substituent group C,

B¹ is NR^(7a), and B² is CH₂, and

R^(7a) is a group shown below:

(wherein substituent group C, R^(E6), and m are same as those of item1).

(Item 15)

The compound according to any one of items 1 to 9, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B¹ is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),

R^(9a) is hydrogen, and R^(11a) is hydrogen, and

i) either R^(8a) or R^(10a) is

a group shown below:

(wherein R^(E6) and m are same as those of item 1); and

ii) the other of R^(8a) or R^(10a) is

hydrogen, or lower alkyl optionally substituted by substituent group C(substituent group C is same as that of item 1).

(Item 16)

The compound according to any one of items 1 to 7, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B is CR^(5a)R^(6a), and B² is NR^(7a),

R^(6a) is hydrogen,

R^(3a) and R^(7a) are taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, and

R^(5a) is hydrogen, lower alkyl optionally substituted by substituentgroup C, carbocyclic group optionally substituted by substituent groupC, carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC,

—Y—S—R^(D1),

—C(═O)—C(═O)—R^(D2), or

—C(═O)—N(R^(D3))(RD⁴)

(wherein RD, R^(D2), R^(D3), R^(D4), Y, substituent group C andsubstituent group D are same as those of item 1).

(Item 17)

The compound according to item 16, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(5a) is hydrogen, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C

(wherein substituent group C is same as that of item 1).

(Item 18)

The compound according to any one of items 1 to 7, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein B is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a),

R^(9a) is hydrogen, and R^(10a) is hydrogen,

R^(3a) and R^(11a) are taken together with an adjacent atom to formheterocycle optionally substituted by substituent group D, and

R^(8a) is hydrogen, lower alkyl optionally substituted by substituentgroup C, carbocyclic group optionally substituted by substituent groupC, carbocycle lower alkyl optionally substituted by substituent group C,carbocycleoxy lower alkyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC,

—Y—S—R^(D1),

—C(═O)—C(═O)—R^(D2), or

—C(═O)—N(R^(D3))(R^(D4))

(wherein R^(D1), R^(D2), R^(D3), R^(D4), Y, substituent group C andsubstituent group D are same as those of item 1).

(Item 19)

The compound according to item 18, or the pharmaceutically acceptablesalt thereof or the solvate thereof,

wherein R^(8a) is hydrogen, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C

(wherein substituent group C is same as that of item 1).

(Item 20)

The compound according to any one of items 16 to 19, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein substituent group D is carbocyclic group optionally substitutedby substituent group C, heterocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, or heterocycle lower alkyl optionally substitutedby substituent group C

(wherein substituent group C is same as that of item 1).

(Item 21)

The compound according to any one of items 1 to 20, or thepharmaceutically acceptable salt thereof or the solvate thereof,

wherein P^(R) is a group selected from the following formulae a) to y):

—C(═O)—P^(R0),  a)

—C(═O)—P^(R1),  b)

—C(═O)-L-P^(R1),  c)

—C(═O)-L-O—P^(R1),  d)

—C(═O)-L-O-L-O—P^(R1),  e)

—C(═O)-L-O—C(═O)—P^(R1),  f)

—C(═O)—O—P^(R2),  g)

—C(═O)—N(P^(R2))₂,  h)

—C(═O)—O-L-O—P^(R2),  i)

—CH₂—O—P^(R3),  j)

—CH₂—O-L-O—P^(R3),  k)

—CH₂—O—C(═O)—P^(R3),  l)

—CH₂—O—C(═O)—O—P^(R3),  m)

—CH(—CH₃)—O—C(═O)—O—P^(R3),  n)

—CH₂—O—C(═O)—N(—K)—P^(R3),  o)

—CH₂—O—C(═O)—O-L-O—P^(R3),  p)

—CH₂—O—C(═O)—O-L-N(P^(R3))₂,  q)

—CH₂—O—C(═O)—N(—K)-L-O—P^(R3),  r)

—CH₂—O—C(═O)—N(—K)-L-N(P^(R3))₂,  s)

—CH₂—O—C(═O)—O-L-O-L-O—P^(R3),  t)

—CH₂—O—C(═O)—O-L-N(—K)—C(═O)—P^(R3),  u)

—CH₂—O—P(═O)(—OH)₂,  v)

—CH₂—O—P(═O)(—OBn)₂,  w)

—CH₂—P^(R4) (except for a benzyl group)  x)

—C(═N⁺P^(R5) ₂)(—NP^(R5) ₂)  y)

(wherein L is straight or branched lower alkylene, or straight orbranched lower alkenylene,

K is hydrogen, or straight or branched lower alkylene,

P^(R0) is lower alkyl optionally substituted by substituent group F, orlower alkenyl optionally substituted by substituent group F,

P^(R1) is carbocyclic group optionally substituted by substituent groupF, heterocyclic group optionally substituted by substituent group F,lower alkyl amino optionally substituted by substituent group F, orlower alkylthio optionally substituted by substituent group F,

P^(R2) is lower alkyl optionally substituted by substituent group F,carbocyclic group optionally substituted by substituent group F, orheterocyclic group optionally substituted by substituent group F,

P^(R3) is lower alkyl optionally substituted by substituent group F,carbocyclic group optionally substituted by substituent group F,heterocyclic group optionally substituted by substituent group F, loweralkyl amino optionally substituted by substituent group F, carbocyclelower alkyl optionally substituted by substituent group F, heterocyclelower alkyl optionally substituted by substituent group F, or loweralkylsilyl,

P^(R4) is carbocyclic group optionally substituted by substituent groupF, or heterocyclic group optionally substituted by substituent group F,and

P^(R5) is lower alkyl optionally substituted by substituent group F.

Substituent group F; oxo, lower alkyl, hydroxy lower alkyl, amino, loweralkylamino, carbocycle lower alkyl, lower alkylcarbonyl, halogen,hydroxy, carboxy, lower alkylcarbonylamino, lower alkylcarbonyloxy,lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro).

(Item 22)

A pharmaceutical composition containing a compound according to any oneof items 1 to 21, or a pharmaceutically acceptable salt thereof or asolvate thereof.

(Item 23)

The pharmaceutical composition according to item 22 which exhibits antiinfluenza activity.

(Item 24)

The pharmaceutical composition according to item 22 which exhibitscap-dependent endonuclease inhibitory activity.

(Item 25)

The pharmaceutical composition according to item 22 for treating and/orpreventing influenza infectious disease.

(Item 26)

A cap-dependent endonuclease inhibitor containing a compound accordingto any one of items 1 to 21, or a pharmaceutically acceptable saltthereof or a solvate thereof.

The present invention further provides a method for treating orpreventing influenza infectious disease using the prodrug compound andthe compound which exhibits anti influenza activity. The presentinvention further provides a parent compound of the prodrug compound.The parent compound is effective as an anti-influenza agent or anintermediate of the prodrug compound.

Effect of the Invention

The compound according to the present invention has an inhibitoryactivity on cap-dependent endonuclease. More preferred compound is aprodrug, and the prodrug becomes a parent compound having an inhibitoryactivity on cap-dependent endonuclease in vivo after administration,thus is effective as a therapeutic agent and/or preventive agent forinfluenza infectious disease.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a result of measuring changes in the plasma concentration ofReference example 301, for compound of Example 114 obtained byconverting into a prodrug compound of Reference example 301 that is aparent compound, after oral administration to rat under non-fastingconditions.

FIG. 2 is a graph showing an average of the changes in the plasmaconcentration when the measurement shown in FIG. 1 is performed threetimes.

FIG. 3 is a result of measuring changes in the plasma concentration ofReference example 301, for compound of Example 204 obtained byconverting into a prodrug compound of Reference example 301 that is aparent compound, after oral administration to rat under non-fastingconditions.

FIG. 4 is a graph showing an average of the changes in the plasmaconcentration when the measurement shown in FIG. 3 is performed threetimes.

BEST MODE FOR CARRYING OUT THE INVENTION

The meaning of each term used in the present description is explainedbelow. Each term is used in a unified sense, and is used in the samesense when used alone, or when used in combination of other term.

“Optionally substituted by substituent group C” means that an arbitraryposition may be substituted by one, two or more same or differentsubstituents selected from substituent group C.

“Optionally substituted by substituent group D”, and “optionallysubstituted by substituent group F” are also as described above.

“Prodrug” in the present description refers to a compound represented byformula (I) in the following reaction formula:

(wherein each symbol is same as that of item 1)

or a pharmaceutically acceptable salt thereof or a solvate thereof, andmeans a compound showing cap-dependant endonuclease (CEN) inhibitoryactivity and/or CPE inhibitory effect by being converted into a compoundrepresented by formula (II) by a decomposition reaction caused bydrug-metabolizing enzymes, hydrolases, gastric acids, enterobacteria,etc. under physiological conditions in vivo.

The prodrug more preferably means a compound in which bioavailabilityand/or AUC (area under the blood concentration curve) in in vivoadministration is improved more than those of the compound representedby formula (II).

Therefore, the prodrug is efficiently absorbed into the body in thestomach and/or intestines after in vivo administration (for example,oral administration), then converted into the compound represented byformula (II). Thus, the prodrug preferably shows an effect of treatingand/or preventing influenza higher than the compound represented byformula (II).

“Group to form a prodrug” in the present description refers to a “P^(R)”group in the formula (I), in the following reaction formula:

(wherein each symbol is same as that of item 1)

and —OP^(R) group is converted into —OH group in the formula (II) by adecomposition reaction caused by drug-metabolizing enzymes, hydrolases,gastric acids, enterobacteria, etc. under physiological conditions invivo. The “group to form a prodrug” more preferably means a group thatimproves bioavailability and/or AUC (area under the blood concentrationcurve) of the compound represented by formula (II) by being added to thecompound represented by formula (II).

Examples of the group to form a prodrug include the groups described inProg. Med. 5: 2157-2161 (1985) and Supplied by The British Library—“Theworld's Knowledge”.

The “P^(R)” group in —OP^(R) group in the formula (I) may be a groupconverted into —OH group in vivo. Preferably the groups selected fromvarious substituted carbonyl groups, substituted lower alkyl oxy groups(e.g., substituted oxymethyl), optionally substituted cyclic group loweralkyl (e.g., optionally substituted cyclic methyl group), and optionallysubstituted imino lower alkyl (e.g., optionally substituted iminomethyl) are exemplified, and examples preferably include a groupselected from the following formulae a) to y).

—C(═O)—P^(R0),  a)

—C(═O)—P^(R1),  b)

—C(═O)-L-P^(R1),  c)

—C(═O)-L-O—P^(R1),  d)

—C(═O)-L-O-L-O—P^(R1),  e)

—C(═O)-L-O—C(═O)—P^(R1),  f)

—C(═O)—O—P^(R2),  g)

—C(═O)—N(P^(R2))₂,  h)

—C(═O)—O-L-O—P^(R2),  i)

—CH₂—O—P^(R3),  j)

—CH₂—O-L-O—P^(R3),  k)

—CH₂—O—C(═O)—P^(R3),  l)

—CH₂—O—C(═O)—O—P^(R3),  m)

—CH(—CH₃)—O—C(═O)—O—P^(R3),  n)

—CH₂—O—C(═O)—N(—K)—P^(R3),  o)

—CH₂—O—C(═O)—O-L-O—P^(R3),  p)

—CH₂—O—C(═O)—O-L-N(P^(R3))₂,  q)

—CH₂—O—C(═O)—N(—K)-L-O—P^(R3),  r)

—CH₂—O—C(═O)—N(—K)-L-N(P^(R3))₂,  s)

—CH₂—O—C(═O)—O-L-O-L-O—P^(R3),  t)

—CH₂—O—C(═O)—O-L-N(—K)—C(═O)—P^(R3),  u)

—CH₂—O—P(═O)(—OH)₂,  v)

—CH₂—O—P(═O)(—OBn)₂,  w)

—CH₂—P^(R4)  x)

—C(═N⁺P^(R5) ₂)(—NP^(R5) ₂)  y)

(wherein L is straight or branched lower alkylene,

K is hydrogen, or straight or branched lower alkylene, or straight orbranched lower alkenylene,

P^(R0) is lower alkyl optionally substituted by substituent group F, orlower alkenyl optionally substituted by substituent group F,

P^(R1) is carbocyclic group optionally substituted by substituent groupF, heterocyclic group optionally substituted by substituent group F,lower alkyl amino optionally substituted by substituent group F, orlower alkylthio optionally substituted by substituent group F,

P^(R2) is lower alkyl optionally substituted by substituent group F,carbocyclic group optionally substituted by substituent group F, orheterocyclic group optionally substituted by substituent group F,

P^(R3) is lower alkyl optionally substituted by substituent group F,carbocyclic group optionally substituted by substituent group F,heterocyclic group optionally substituted by substituent group F, loweralkyl amino optionally substituted by substituent group F, carbocyclelower alkyl optionally substituted by substituent group F, heterocyclelower alkyl optionally substituted by substituent group F, or loweralkylsilyl,

P^(R4) is carbocyclic group optionally substituted by substituent groupF, or heterocyclic group optionally substituted by substituent group F,and

P^(R5) is lower alkyl optionally substituted by substituent group F.

Substituent group F; oxo, lower alkyl, hydroxy lower alkyl, amino, loweralkylamino, carbocycle lower alkyl, lower alkylcarbonyl, halogen,hydroxy, carboxy, lower alkylcarbonylamino, lower alkylcarbonyloxy,lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro)

As the group to form a prodrug, the “P^(R)” group in —OP^(R) group inthe formula (I) is preferably a group selected from the following b),k), l), and m).

—C(═O)—P^(R1),  b)

—CH₂—O—C(═O)—P^(R3),  l)

—CH₂—O—C(═O)—O—P^(R3),  m)

—CH(—CH₃)—O—C(═O)—O—P^(R3),  n)

(wherein each symbol is same as above)

“Converted into a prodrug” in the present description means that, asshown in the following reaction formula:

(wherein each symbol is same as that of item 1)

a hydroxy group in the formula (II) or pharmaceutically acceptable saltthereof or a solvate thereof is converted into —OP^(R) group.

“Parent compound” in the present description means a compound to be asource before synthesizing the “prodrug” and/or a compound released fromthe “prodrug” by the reaction by enzymes, a gastric acid, and the likeunder physiological conditions in vivo, and specifically means acompound shown by the formula (II), or pharmaceutically acceptable saltthereof or a solvate thereof.

“Halogen” includes fluorine, chlorine, bromine and iodine. Preferable isfluorine, chlorine and bromine. “Lower alkyl” includes straight orbranched alkyl of a carbon number of 1 to 15, preferably a carbon numberof 1 to 10, more preferably a carbon number of 1 to 6, furtherpreferably a carbon number of 1 to 4, and examples include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl,n-octyl, isooctyl, n-nonyl and n-decyl etc. Examples of a preferableembodiment of “lower alkyl” include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Examples of afurther preferable embodiment include methyl, ethyl, n-propyl,isopropyl, and tert-butyl.

“Lower alkenyl” includes straight or branched alkenyl of a carbon numberof 2 to 15, preferably a carbon number of 2 to 10, more preferably acarbon number of 2 to 6, further preferably a carbon number of 2 to 4,having one or more double bonds at an arbitrary position. Specifically,lower alkenyl includes vinyl, allyl, propenyl, isopropenyl, butenyl,isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl,hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl etc.Examples of a preferable embodiment of “lower alkenyl” include vinyl,allyl, propenyl, isopropenyl, and butenyl.

“Lower alkynyl” includes straight or branched alkynyl of a carbon numberof 2 to 10, preferably a carbon number of 2 to 8, further preferably acarbon number of 3 to 6, having one or more triple bonds at an arbitraryposition. Specifically, lower alkynyl includes ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc.These may further have a double bond at an arbitrary position. Examplesof a preferable embodiment of “lower alkynyl” include ethynyl, propynyl,butynyl, and pentynyl.

A lower alkyl part of “lower alkyloxy”, “lower alkylcarbonyl”, “loweralkyloxycarbonyl”, “carbocycle lower alkyl”, “heterocycle lower alkyl”,“carbocycleoxy lower alkyl”, “heterocycleoxy lower alkyl”, “halogenolower alkyl”, “carbocycle lower alkyloxy”, “heterocycle lower alkyloxy”,“halogeno lower alkyloxy”, “lower alkyloxy lower alkyl”, “lower alkyloxylower alkyloxy”, “lower alkylcarbonyl”, “lower alkyloxycarbonyl”, “loweralkylamino”, “lower alkylcarbonylamino”, “lower alkylaminocarbonyl”,“lower alkylsulfonyl”, “lower alkylsulfonylamino”, “lower alkylthio”,“hydroxy lower alkyl”, “carbocycle lower alkyloxy lower alkyl”,“heterocycle lower alkyloxy lower alkyl”, “lower alkylcarbonyloxy”,“halogeno lower alkylcarbonylamino”, and “lower alkylsulfinyl” is thesame as the “lower alkyl” as described above.

A lower alkenyl part of “lower alkenyloxy” is the same as the “loweralkenyl” as described above.

A halogen part of “halogeno lower alkyl”, “halogeno lower alkyloxy”, and“halogeno lower alkylcarbonylamino” is the same as the “halogen”.Herein, an arbitrary position on an alkyl group of “lower alkyl”, “loweralkyloxy”, and “lower alkylcarbonylamino” may be substituted by same ordifferent one or plural halogen atoms, respectively.

“Carbocyclic group” or “carbocycle” means carbocyclic group of a carbonnumber of 3 to 20, preferably a carbon number of 3 to 16, morepreferably a carbon number of 4 to 12, and includes cycloalkyl,cycloalkenyl, aryl and a non-aromatic condensed carbocyclic group, etc.

Specifically, “cycloalkyl” is carbocyclic group of a carbon number of 3to 16, preferably a carbon number of 3 to 12, more preferably a carbonnumber of 4 to 8, and examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl andcyclodecyl, etc.

Specifically, “cycloalkenyl” includes cycloalkenyl having one or moredouble bonds at an arbitrary position in the cycloalkyl ring, andexamples include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptynyl, cyclooctynyl and cyclohexadienyl, etc.

Specifically, “aryl” means an aromatic carbocyclic group, and includesphenyl, naphthyl, anthryl and phenanthryl, etc. and, particularly,phenyl is preferable.

Specifically, “non-aromatic condensed carbocyclic group” includes agroup in which two or more cyclic groups selected from the “cycloalkyl”,the “cycloalkenyl” and the “aryl” are condensed, and examples includeindanyl, indenyl, tetrahydronaphthyl, fluorenyl, adamantyl, and groupsshown below

etc.

Examples of a preferable embodiment of “carbocyclic group” or“carbocycle” include cycloalkyl, aryl and a non-aromatic condensedcarbocyclic group, specifically examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, andgroups shown below

etc.

A carbocyclic part of “carbocycle lower alkyl”, “carbocycle loweralkyloxy”, “carbocycleoxy lower alkyl”, “carbocyclecarbonyl”,“carbocycleoxy”, “carbocycleoxycarbonyl” and “carbocycle lower alkyloxylower alkyl” is the same as the “carbocyclic group” or the “carbocycle”as described above.

“Heterocyclic group” or “heterocycle” includes heterocyclic group suchas heteroaryl, a non-aromatic heterocyclic group, a bicyclic condensedheterocyclic group, a tricyclic condensed heterocyclic group, atetracyclic condensed heterocyclic group, etc., having one or more sameor different hetero atoms arbitrarily selected from O, S and N in aring.

Specifically, “heteroaryl” includes a 5- to 6-membered aromatic cyclicgroup such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl,thienyl, isooxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl,thiadiazolyl, etc.

Specifically, “non-aromatic heterocyclic group” includes a 4- to8-membered non-aromatic heterocyclic group such as dioxanyl, thiiranyl,oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino,thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl,tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl,tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl,hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl,hexahydropyrimidinyl, dioxolanyl, dioxolyl, oxabicycloheptanyl, etc.

Specifically, “bicyclic condensed heterocyclic group” includes a cyclicgroup including at least one 4- to 8-membered aromatic or non-aromaticheterocyclic group such as indolyl, isoindolyl, indazolyl, indolizinyl,indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl,pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl,benzisooxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl,benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl,benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl,thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl,imidazopyridyl, pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl,pyrazolotrianizyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl,pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl,naphthyridinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl,dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl,benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl,dihydrobenzodioxynyl, dihydrobenzooxezinyl, dihydrobenzodioxepinyl,dihydrothienodioxynyl, etc.

Specifically, “tricyclic condensed heterocyclic group” includes a cyclicgroup including at least one 4- to 8-membered aromatic or non-aromaticheterocyclic group such as carbazolyl, acridinyl, xanthenyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl,imidazoquinolyl, tetrahydrocarbazolyl, and groups shown below

etc.

Examples of a preferable embodiment of “heterocyclic group” include 5-to 6-membered heteroaryl, a non-aromatic heterocyclic group and atricyclic condensed heterocyclic group.

A heterocyclic part of “heterocycle lower alkyl”, “heterocycle loweralkyloxy”, “carbocycleoxy lower alkyl”, “heterocyclecarbonyl”,“heterocycleoxy”, “heterocycleoxycarbonyl”, and “heterocycle loweralkyloxy lower alkyl” is the same as the “heterocyclic group” or the“heterocycle” as described above.

“Heterocyclic group substituted by oxo” means the “heterocyclic group”as described above, substituted by oxo as shown below. Groups shownbelow

are exemplified.

“Straight or branched lower alkylene” is divalent “lower alkyl” asdescribed above, and includes, for example, methylene, ethylene,propylene, butylene, isobutylene, pentylene, heptylene,dimethylmethylene, ethylmethylmethylene, 1,2-dimethylethylene, etc.

Examples of “lower alkyloxy” include methoxy, ethoxy, propyloxy,isopropyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy,isopentyloxy, hexyloxy, etc. Examples of a preferable embodiment includemethoxy, ethoxy, propyloxy, isopropyloxy, and tert-butyloxy.

Examples of “lower alkylcarbonyl” include methylcarbonyl, ethylcarbonyl,propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl,sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl,etc. Examples of a preferable embodiment include methylcarbonyl,ethylcarbonyl, and propylcarbonyl. Examples of “lower alkyloxycarbonyl”include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl,isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl,sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl,hexyloxycarbonyl, etc. Examples of a preferable embodiment includemethyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.

“Carbocycle lower alkyl” represents lower alkyl substituted by one, twoor more carbocyclic groups, and examples of “carbocycle lower alkyl”include benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, naphthylmethyl, a group shown below

etc.

Examples of a preferable embodiment include benzyl, phenethyl, andbenzhydryl.

“Heterocycle lower alkyl” represents lower alkyl substituted by one, twoor more heterocyclic groups, and also includes heterocycle lower alkylin which an alkyl part is substituted by carbocyclic group. Examples of“heterocycle lower alkyl” include pyridylmethyl,tetrahydropyranylmethyl, furanylmethyl, morpholinylethyl,imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl,isooxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl,isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl,piperidinylmethyl, piperazinylmethyl, groups shown below

etc.

Examples of a preferable embodiment include pyridylmethyl,tetrahydropyranylmethyl, furanylmethyl, and morpholinylethyl.

Examples of “carbocycleoxy lower alkyl” include phenyloxymethyl,phenyloxyethyl, cyclopropyloxymethyl, cyclopropyloxyethyl,cyclobutyloxymethyl, cyclobutyloxyethyl, cyclohexyloxymethyl,cyclohexyloxyethyl, etc. Examples of a preferable embodiment includephenyloxymethyl, and phenyloxyethyl.

Examples of “heterocycleoxy lower alkyl” include pyridyloxymethyl,pyridyloxyethyl, morpholinyloxymethyl, morpholinyloxyethyl,benzoxazolyloxymethyl, etc. Examples of a preferable embodiment includepyridyloxymethyl, morpholinyloxymethyl, etc.

“Carbocycle lower alkyloxy” represents lower alkyloxy in which an alkylpart is substituted by one, two or more carbocyclic groups, and examplesof “carbocycle lower alkyloxy” include phenylmethyloxy, phenylethyloxy,cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy,cyclohexylmethyloxy, etc. Examples of a preferable embodiment includephenylmethyloxy, cyclopropylmethyloxy, etc.

“Heterocycle lower alkyloxy” represents lower alkyloxy in which an alkylpart is substituted by one, two or more heterocyclic groups, and alsoincludes heterocycle lower alkyloxy in which an alkyl part issubstituted by carbocyclic group. Examples of “heterocycle loweralkyloxy” include pyridylmethyloxy, pyridylethyloxy,imidazolylmethyloxy, imidazolylethyloxy, benzoxazolylmethyloxy,benzoxazolylethyloxy, etc.

Examples of “lower alkyloxy lower alkyl” include methoxymethyl,methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, methoxybutyl,ethoxypropyl, ethoxybutyl, isopropyloxymethyl, tert-butyloxymethyl, etc.Examples of a preferable embodiment include methoxymethyl, methoxyethyl,ethoxymethyl, and ethoxyethyl.

Examples of “lower alkyloxy lower alkyloxy” include methoxymethoxy,methoxyethoxy, ethoxymethoxy, ethoxyethoxy, methoxypropyloxy,methoxybutyloxy, ethoxypropyloxy, ethoxybutyloxy, isopropyloxymethyloxy,tert-butyloxymethyloxy, etc. Examples of a preferable embodiment includemethoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.

Examples of “lower alkylamino” include methylamino, dimethylamino,ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino,N-methyl-N-ethylamino, N-isopropyl-N-ethylamino, etc. Examples of apreferable embodiment include methylamino, dimethylamino, ethylamino,and diethylamino.

Examples of “lower alkylcarbonylamino” include methylcarbonylamino,ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino,tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino,etc. Examples of a preferable embodiment include methylcarbonylamino,and ethylcarbonylamino.

Examples of “lower alkylaminocarbonyl” include methylaminocarbonyl,dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl,isopropylaminocarbonyl, N,N-diisopropylaminocarbonyl,N-methyl-N-ethylaminocarbonyl, N-isopropyl-N-ethylaminocarbonyl, etc.Examples of a preferable embodiment include methylaminocarbonyl,dimethylaminocarbonyl, ethylaminocarbonyl, and diethylaminocarbonyl.

Examples of “lower alkylsulfonyl” include methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl,sec-butylsulfonyl, etc. Examples of a preferable embodiment includemethylsulfonyl, and ethylsulfonyl.

Examples of “lower alkylsulfonylamino” include methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino,tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino,etc. Examples of a preferable embodiment include methylsulfonylamino,and ethylsulfonylamino.

Examples of “lower alkenyloxy” include ethylenyloxy, 1-propylenyloxy,2-propylenyloxy, 1-butylenyloxy, 2-butylenyloxy, 3-butylenyloxy, etc.

Examples of “halogeno lower alkyl” include monofluoromethyl,monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl,monochloromethyl, trifluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl,1,1,1-trifluoropropan-2-yl, etc. Examples of a preferable embodimentinclude trifluoromethyl, trichloromethyl, 1,1,1-trifluoropropan-2-yl.

Examples of “halogeno lower alkyloxy” include monofluoromethoxy,monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy,trichloroethoxy, etc. Examples of a preferable embodiment includetrifluoromethoxy, and trichloromethoxy.

Examples of “lower alkylthio” include methylthio, ethylthio, propylthio,etc.

Examples of “hydroxy lower alkyl” include hydroxymethyl, hydroxyethyl,hydroxypropyl, etc.

Examples of “carbocycle lower alkyloxy lower alkyl” includebenzyloxymethyl, benzyloxyethyl, benzhydryloxymethyl, etc.

Examples of “heterocycle lower alkyloxy lower alkyl” includepyridylmethyloxymethyl, pyridylmethyloxyethyl, etc.

Examples of “lower alkylcarbonyloxy” include methylcarbonyloxy,ethylcarbonyloxy, etc.

Examples of “halogeno lower alkylcarbonylamino” includetrifluoromethylcarbonylamino, 2,2,3,3,3-pentafluoropropylcarbonylamino,etc.

Examples of “lower alkylsulfinyl” include methylsulfinyl, ethylsulfinyl,etc.

Examples of “carbocyclecarbonyl” include phenylcarbonyl,naphthylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, etc.

Examples of “carbocycleoxy” include phenyloxy, naphthyloxy,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

Examples of “carbocycleoxycarbonyl” include phenyloxycarbonyl,naphthyloxycarbonyl, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.

Examples of “heterocyclecarbonyl” include pyridylcarbonyl,benzoxazolylcarbonyl, morpholinylcarbonyl, tetrahydropyranylcarbonyl,etc.

Examples of “heterocycleoxy” include pyridyloxy, benzoxazolyloxy,morpholinyloxy, tetrahydropyranyloxy, etc.

Examples of “heterocycleoxycarbonyl” include pyridyloxycarbonyl,benzoxazolyloxycarbonyl, morpholinyloxycarbonyl,tetrahydropyranyloxycarbonyl, etc.

The terms:

“R^(A1) and R^(A2), R^(A15) and R^(A16), as well as R^(A19) and R^(A20),each may be taken together with an adjacent atom to form a heterocycle”,

“R^(B7) and R^(B8), as well as R^(B9) and R^(B10), each may be takentogether with an adjacent atom to form a heterocycle”,

“R^(C7) and R^(C8), as well as R^(B9) and R^(B10), each may be takentogether with an adjacent atom to form a heterocycle”, and

“R^(D5) and R^(D6) may be taken together with an adjacent atom to form aheterocycle” in item 1

mean a heterocycle having N atom, and include, for example, groups shownbelow

etc.

In the present description, (R^(E6))m in the formulae shown below

means that an arbitrary carbon atom or nitrogen atom which canchemically have a substituent on a ring is substituted by m of R^(E6)swhich are same or different.

For example, in the formula below

as shown by a substituent below

(wherein ma+mb+me=m, and R^(E6) is same as above),

it is meant that any hydrogen atom on two benzene rings and a 7-memberedring containing a sulfur atom may be substituted by R^(E6), andrespective R^(E6)s may be the same or different.

And, ma is preferably an integer of 0 to 3, mb is preferably an integerof 0 to 3, and me is preferably an integer of 0 or 1. And, ma is morepreferably an integer of 0 or 1, mb is more preferably an integer of 0or 1, and me is more preferably 0.

For example, in the formula below

substituents shown below

(wherein R^(E6), and m are same as those of item 1) etc. are included.

“B¹ is CR^(5a)R^(6a), and B² is NR^(7a), R^(3a) and R^(7a) may be takentogether with an adjacent atom to form a heterocycle optionallysubstituted by substituent group D” in the formula (I) in item 1represents the formula (I′) shown below:

(wherein P^(R), R^(1a), R^(2a), R^(5a) and R^(6a) are same as those ofitem 1), and indicates that a part of a ring may be substituted by one,two or more same or different substituents selected from substituentgroup D at an arbitrary position. The heterocycle is preferably a 5- to7-membered ring. In addition, “the heterocycle may form a condensedring” indicates that the ring in the formula (I′) may be furthercondensed with a ring, and indicates that substituent group D may bebound to any of the ring in the formula (I′) or the ring which iscondensed with a ring.

Examples of the formula (I′) include compounds shown by the followingformulae

(wherein R^(x), and R^(y) are a substituent selected from substituentgroup D, and P^(R), R^(1a), R^(2a), R^(5a), and R^(6a) are same as thoseof item 1) etc.

“When form a heterocyle” in “B¹ is NR^(7a), and B² is CR^(5a)R^(6a),R^(3a) and R^(6a) may be taken together with an adjacent atom to form aheterocycle optionally substituted by substituent group D” in theformula (I) in item 1 represents the formula (I″) shown below:

(wherein P^(R), R^(1a), R^(2a), R^(5a) and R^(7a) are same as those ofitem 1), and indicates that “Ring” may be substituted by one, two ormore same or different substituents selected from substituent group D atan arbitrary position. The heterocycle is preferably a 5- to 7-memberedring. In addition, “the heterocycle may form a condensed ring” indicatesthat the ring in the formula (I″) may be further condensed with a ring,and indicates that one, two or more of substituent group D may be boundto any of the ring in the formula (I″) or the ring which is condensedwith a ring. Examples of the formula (I″) include compounds shown by thefollowing formulae

(wherein R^(x), and R^(y) are a substituent selected from substituentgroup D, and P^(R), R^(1a), R^(2a), R^(5a), and R^(7a) are same as thoseof item 1) etc.

“When form a carbocycle or heterocyle” in “R^(8a) and R^(10a) may betaken together with an adjacent atom to form a carbocycle or heterocycleoptionally substituted by substituent group D” in the formula (I) initem 1 represents the formula (I″″) shown below:

(wherein P^(R), R^(1a), R^(2a), R^(3a), R^(9a), and R^(11a) are same asthose of item 1), and indicates that “Ring” may be substituted by one,two or more same or different substituents selected from substituentgroup D at an arbitrary position. The carbocycle or the heterocycle ispreferably a 5- to 7-membered ring. Examples of the formula (I″″)include compounds shown by the following formula

(wherein R^(x) is a substituent selected from substituent group D, andP^(R), R^(1a), R^(2a), R^(3a), R^(9a), and R^(11a) are same as those ofitem 1) etc.

Further, “R^(3a) and R^(11a) may be taken together with an adjacent atomto form a heterocycle optionally substituted by substituent group D, andthe heterocycle may form a condensed ring” represents the formula (I′″″)shown below:

(wherein P^(R), R^(1a), R^(2a), R^(8a), R^(9a), and R^(10a) are same asthose of item 1), and indicates that “Ring” may further form a condensedring, and the same or different substituents selected from substituentgroup D may be bound to any of the ring in the formula (I′″″) or thering which is condensed with a ring at an arbitrary position. Theheterocycle is preferably a 5- to 7-membered ring. Examples of theformula (I′″″) include compounds shown by the following formulae

(wherein R^(x), and R^(y) are a substituent selected from substituentgroup D, and P^(R), R^(1a), R^(2a), R^(8a), R^(9a), and R^(10a) are sameas those of item 1) etc.

“Solvate” includes, for example, a solvate with an organic solvent, ahydrate, etc. Preferred embodiment is a hydrate or alcoholate, and morepreferred embodiment is a hydrate. When a hydrate is formed, thecompound may be coordinated with an arbitrary number of water molecules.Examples include hemihydrate (1 water molecule is coordinated to 2molecules of the present compound), monohydrate (1 water molecule iscoordinated to 1 molecule of the present compound), dihydrate (2 watermolecules are coordinated to 1 molecule of the present compound),trihydrate (3 water molecules are coordinated to 1 molecule of thepresent compound), etc. The same shall apply when an alcoholate isformed. Examples of alcohol when an alcoholate is formed includemethanol, ethanol, isopropanol, etc.

The compound of the present invention includes a pharmaceuticallyacceptable salt. Examples include salts with an alkali metal (lithium,sodium or potassium, etc.), an alkaline earth metal (magnesium orcalcium, etc.), ammonium, an organic base and an amino acid, or saltswith an inorganic acid (hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid or hydroiodic acid, etc.), and anorganic acid (acetic acid, trifluoroacetic acid, citric acid, lacticacid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelicacid, glutaric acid, malic acid, benzoic acid, phthalic acid,benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid orethanesulfonic acid, etc.). These salts can be formed by the methodwhich is usually performed.

Examples of preferred salt of the formula (I) in the present inventioninclude hydrochloride, hydrobromate, acetate, sulfate, etc.

In addition, the compound of the present invention is not limited to aparticular isomer, but includes all possible isomers (keto-enol isomer,imine-enamine isomer, diastereoisomer, optical isomer and rotationisomer, etc.) and racemic bodies.

The formula (I) in the present invention is not limited to a particularisomer, but includes all possible isomers and racemic bodies. Forexample, they also contain a tautomer and a steric isomer as shownbelow.

(wherein each symbol is same as above)

(wherein each symbol is same as above)

Further, one or more hydrogen atoms, carbon atoms or other atoms of thecompound of the formula (I) can be substituted by an isotope of ahydrogen atom, a carbon atom or other atoms, respectively.

In addition, the compound of the formula (I) includes all radioactivelabeled bodies thereof. Such the “radioactive labeling” and “radioactivelabeled form” of the compound of the formula (I) are included in thepresent invention, respectively, and are useful as a study and/ordiagnostic tool in metabolized drug dynamic state study and bindingassay.

Examples of an isotope which can be incorporated into the compound ofthe formula (I) of the present invention include a hydrogen atom, acarbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, asulfur atom, a fluorine atom and a chlorine atom, such as ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

A particularly preferable example of an isotope which can beincorporated into the compound of the formula (I) of the presentinvention is ²H (i.e. heavy hydrogen atom), and can be prepared by themethod shown in Reference examples of the present description, or themethod well-known in the art. In addition, a heavy hydrogen atom isexpressed as “D” in Reference examples of the present description.Compound of the formula (I) of the present invention in which a hydrogenatom has been converted into a heavy hydrogen atom are excellent inrespect of bioavailability, metabolism safety, drug efficacy, andtoxicity as compared with unconverted forms, in some cases, and can beuseful as medicaments.

Examples of “lower alkyl optionally substituted by substituent group C”include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,pentan-2-yl, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl,carboxypropyl, ethoxycarbonylpropyl, cyanomethyl, cyanoethyl,fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,ethyloxycarbonylethyl, methoxymethyl, dimethoxymethyl, methoxyethyl,methoxypropyl, ethoxyethyl, 1-methyl-1-methoxymethyl, propyloxymethyl,aminopropyl, dimethylaminomethyl, aminomethyl, aminoethyl,dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl,dimethylaminopropyl, cyclopropylmethyloxymethyl,methylsulfonylaminomethyl, methylaminocarbonylethyl,1,1,1-trifluoropropan-2-yl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl,1,1,1-trifluoropropyl, trifluoromethyloxyethyl,trifluoromethylcarbonylaminomethyl, methylsulfonylethyl,methylcarbonyloxyethyl, and groups shown below

etc.

Examples of “lower alkyl optionally substituted by substituent group F”include hydroxyethyl, methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, iso-butyl, sec-butyl, pentan-2-yl, hydroxymethyl,hydroxyethyl, carboxymethyl, carboxyethyl, carboxypropyl,ethoxycarbonylpropyl, and groups shown below

Examples of “lower alkenyl optionally substituted by substituent groupC” include ethylenyl, 3-methylbuten-2-yl, carboxyethylenyl,hydroxyethylenyl, difluoroethylenyl, 1-propen-2-yl, etc.

Examples of “lower alkynyl optionally substituted by substituent groupC” include 1-propynyl, 1-butynyl, 3,3,3-trifluoromethylpropynyl,3-hydroxy-propynyl, etc.

Examples of “lower alkyloxy optionally substituted by substituent groupC” include methyloxy, ethyloxy, trifluoromethyloxy, trichloromethyloxy,hydroxymethyloxy, hydroxyethyloxy, carboxymethyloxy, carboxyethyloxy,etc.

Examples of “lower alkenyloxy optionally substituted by substituentgroup C” include 3-fluoro-1-propenyloxy, ethylenyl, carboxyethylenyl,hydroxyethylenyloxy, difluoroethylenyloxy, etc.

Examples of “lower alkylcarbonyl optionally substituted by substituentgroup C” include methylcarbonyl, ethylcarbonyl, propylcarbonyl,isopropylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl,trifluoromethylcarbonyl, 2,2,2-trifluoromethylcarbonyl,carboxymethylcarbonyl, etc.

Examples of “lower alkyloxycarbonyl optionally substituted bysubstituent group C” include methyloxycarbonyl, ethyloxycarbonyl,trifluoromethyl oxycarbonyl, trichloromethyloxycarbonyl,hydroxymethyloxycarbonyl, hydroxyethyloxycarbonyl,carboxymethyloxycarbonyl, etc.

Examples of “carbocyclic group optionally substituted by substituentgroup C” include phenyl, naphthyl, anthracenyl, phenanthracenyl,adamantyl, 1-hydroxyadamantyl, 2-hydroxyadamantyl, 3-methylphenyl,4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, fluorocyclopropyl, difluorocyclobutanyl,difluorocyclohexyl, and groups shown below

(wherein R^(E6) represents a group selected from substituent group C,and m of R^(E6)s may be the same or different) etc.

Examples of “carbocyclic group optionally substituted by substituentgroup F” include phenyl, naphthyl, 3-methylphenyl, 4-methylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,4-chlorophenyl, 4-fluorophenyl, 1,5-difluorophenyl, etc.

Examples of “carbocycle lower alkyl optionally substituted bysubstituent group C” include cyclopropylmethyl, 4-hydroxybenzyl,cyclopentylmethyl, benzyl, 2-aminobenzyl, 2-cyanobenzyl, 2-fluorobenzyl,4-fluorobenzyl, 2-trifluoromethylbenzyl, 1,3,5-trifluorobenzyl,3,4,5-trifluorobenzyl, 4-methoxybenzyl, 2,4-difluorobenzyl,2-fluoro-3-chlorobenzyl, benzhydryl, 4-phenylbenzyl, phenethyl,phenylpropyl, 4-methylcarbonylaminobenzyl, 3,4-dichlorobenzyl,4-chloro-2-fluorobenzyl, 3,5-dihydroxybenzyl, and groups shown below

etc.

Examples of “carbocycle lower alkyl optionally substituted bysubstituent group F” include cyclopropylmethyl, 4-hydroxybenzyl,cyclopentylmethyl, benzyl, 2-aminobenzyl, 2-cyanobenzyl, 2-fluorobenzyl,4-fluorobenzyl, 2-trifluoromethylbenzyl, 1,3,5-trifluorobenzyl,3,4,5-trifluorobenzyl, 4-methoxybenzyl, 2,4-difluorobenzyl,2-fluoro-3-chlorobenzyl, benzhydryl, 4-phenylbenzyl, phenethyl,phenylpropyl, 4-methylcarbonylaminobenzyl, 3,4-dichlorobenzyl,4-chloro-2-fluorobenzyl, 3,5-dihydroxybenzyl, etc.

Examples of “carbocycleoxy lower alkyl optionally substituted bysubstituent group C” include 4-hydroxyphenyloxymethyl,4-hydroxyphenyloxyethyl, cyclopropyloxymethyl, cyclopentyloxymethyl,4-fluorophenyloxymethyl, 4-fluorophenyloxyethyl,4-trifluoromethylphenyloxymethyl, 4-trifluoromethylphenyloxyethyl,4-methoxyphenyloxymethyl, 4-methoxyphenyloxyethyl, etc.

Examples of “carbocyclecarbonyl optionally substituted by substituentgroup C” include phenylcarbonyl, 4-fluorophenylcarbonyl,4-trifluoromethylphenylcarbonyl, 4-methoxyphenylcarbonyl,cyclopropylcarbonyl, etc.

Examples of “carbocycleoxy optionally substituted by substituent groupC” include phenyloxy, cyclopropyloxy, cyclopentyloxy, 4-fluorophenyloxy,4-trifluoromethylphenyloxy, 4-methoxyphenyloxy, etc.

Examples of “carbocycleoxycarbonyl optionally substituted by substituentgroup C” include phenyloxycarbonyl, cyclopropyloxycarbonyl,cyclopentyloxycarbonyl, 4-fluorophenyloxycarbonyl,4-trifluoromethylphenyloxycarbonyl, 4-methoxyphenyloxycarbonyl, etc.

Examples of “heterocyclic group optionally substituted by substituentgroup C” include pyrimidinyl, pyridyl, benzoxazolyl, morpholinyl,tetrahydropyranyl, furyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl,methylpyrrolidinyl, isopropylpyrrolidinyl, methylsulfonylpyrrolidinyl,hydroxyethylpyrrolidinyl, methylpiperidinyl, methylpiperazinyl,tetrahydrofuryl, and groups shown below

(wherein R^(E6) represents a group selected from substituent group C,and m of R^(E6)s may be the same or different) etc.

Examples of “heterocyclic group optionally substituted by substituentgroup F” include morpholinyl, pyridyl, methyl-1,3-dioxol-2-one,trimethyl-2-oxabicyclo[2.2.1]heptan-3-one, pyrrolidinyl,methyl-pyrrolidine-2-carboxylate, tetrahydropyranyl,hydroxymethylpyrrolidinyl, etc.

Examples of “heterocycle lower alkyl optionally substituted bysubstituent group C” include tetrahydropyranylmethyl, pyridylmethyl,isoxazolylmethyl, 5-methyl-isoxazolylmethyl, 3-methyl-oxadiazolylmethyl,indolylmethyl, benzothiophenylmethyl, 5-chlorobenzothiophenylmethyl,thiazolylmethyl, 2-methylthiazolylmethyl, pyrazolylmethyl,2-methylpyrazolylmethyl, dithiophenylmethyl, tetrazolylmethyl,quinazolylmethyl, morpholinylmethyl, and groups shown below

etc.

Examples of “heterocycle lower alkyl optionally substituted bysubstituent group F” include tetrahydropyranylmethyl, pyridylmethyl,isoxazolylmethyl, 5-methyl-isoxazolylmethyl, 3-methyl-oxadiazolylmethyl,indolylmethyl, benzothiophenylmethyl, 5-chlorobenzothiophenylmethyl,thiazolylmethyl, 2-methylthiazolylmethyl, pyrazolylmethyl,2-methylpyrazolylmethyl, dithiophenylmethyl, tetrazolylmethyl,quinazolylmethyl, morpholinylmethyl, etc.

Examples of “heterocycleoxy lower alkyl optionally substituted by asubstituent group C” include tetrahydropyranyloxymethyl,pyridyloxymethyl, isoxazolyloxymethyl, 5-methyl-isoxazolyloxymethyl,indolyloxymethyl, benzothiophenyloxymethyl,5-chlorobenzothiophenyloxymethyl, thiazolyloxymethyl,2-methylthiazolyloxymethyl, pyrazolyloxymethyl,2-methylpyrazolyloxymethyl, etc.

Examples of “heterocyclecarbonyl optionally substituted by substituentgroup C” include tetrahydropyranylcarbonyl, pyridylcarbonyl,isoxazolylcarbonyl, 5-methyl-isoxazolylcarbonyl, indolylcarbonyl,benzothiophenylcarbonyl, 5-chlorobenzothiophenylcarbonyl,thiazolylcarbonyl, 2-methylthiazolylcarbonyl, pyrazolylcarbonyl,2-methylpyrazolylcarbonyl, etc.

Examples of “heterocycleoxy optionally substituted by substituent C”include tetrahydropyranyloxy, pyridyloxy, isoxazolyloxy,5-methyl-isoxazolyloxy, indolyloxy, benzothiophenyloxy,5-chlorobenzothiophenyloxy, thiazolyloxy, 2-methylthiazolyloxy,pyrazolyloxy, 2-methylpyrazolyloxy, etc.

Examples of “heterocycleoxycarbonyl optionally substituted bysubstituent group C” include tetrahydropyranyloxycarbonyl,pyridyloxycarbonyl, isoxazolyloxycarbonyl,5-methyl-isoxazolyloxycarbonyl, indolyloxycarbonyl,benzothiophenyloxycarbonyl, 5-chlorobenzothiophenyloxycarbonyl,thiazolyloxycarbonyl, 2-methylthiazolyloxycarbonyl,pyrazolyloxycarbonyl, 2-methylpyrazolyloxycarbonyl, etc.

Examples of “lower alkylamino optionally substituted by substituentgroup F” include methylamino, dimethylamino, ethylamino, diethylamino,etc.

Examples of “lower alkylthio optionally substituted by substituent groupF” include methylthio, ethylthio, etc.

Examples of “lower alkylsilyl optionally substituted by substituentgroup F” include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl,etc.

P^(R) in —OP^(R) group is preferably a group converted into —OH group byaction of drug-metabolizing enzymes, hydrolases, gastric acids, and/orenterobacteria, after in vivo administration (for example, oraladministration).

Examples of more preferred embodiment of P^(R) include a group selectedfrom the following formulae b) to x).

—C(═O)—P^(R1),  b)

—C(═O)-L-P^(R1),  c)

—C(═O)-L-O—P^(R1),  d)

—C(═O)-L-O-L-O—P^(R1),  e)

—C(═O)-L-O—C(═O)—P^(R1),  f)

—C(═O)—O—P^(R2),  g)

—C(═O)—N(P^(R2))₂,  h)

—C(═O)—O-L-O—P^(R2),  i)

—CH₂—O—P^(R3),  j)

—CH₂—O-L-O—P^(R3),  k)

—CH₂—O—C(═O)—P^(R3),  l)

—CH₂—O—C(═O)—O—P^(R3),  m)

—CH(—CH₃)—O—C(═O)—O—P^(R3),  n)

—CH₂—O—C(═O)—N(—K)—P^(R3),  o)

—CH₂—O—C(═O)—O-L-O—P^(R3),  p)

—CH₂—O—C(═O)—O-L-N(P^(R3))₂,  q)

—CH₂—O—C(═O)—N(—K)-L-O—P^(R3),  r)

—CH₂—O—C(═O)—N(—K)-L-N(P^(R3))₂,  s)

—CH₂—O—C(═O)—O-L-O-L-O—P^(R3),  t)

—CH₂—O—C(═O)—O-L-N(—K)—C(═O)—P^(R3),  u)

—CH₂—O—P(═O)(—OH)₂,  v)

—CH₂—O—P(═O)(—OBn)₂,  w)

—CH₂—P^(R4)  x)

(wherein L is straight or branched lower alkylene,

K is hydrogen, or straight or branched lower alkylene, or straight orbranched lower alkenylene,

P^(R1) is carbocyclic group optionally substituted by substituent groupF, heterocyclic group optionally substituted by substituent group F,lower alkyl amino optionally substituted by substituent group F, orlower alkylthio optionally substituted by substituent group F,

P^(R2) is lower alkyl optionally substituted by substituent group F,carbocyclic group optionally substituted by substituent group F, orheterocyclic group optionally substituted by substituent group F,

P^(R3) is lower alkyl optionally substituted by substituent group F,carbocyclic group optionally substituted by substituent group F,heterocyclic group optionally substituted by substituent group F, loweralkyl amino optionally substituted by substituent group F, carbocyclelower alkyl optionally substituted by substituent group F, heterocyclelower alkyl optionally substituted by substituent group F, or loweralkylsilyl,

P^(R4) is carbocyclic group optionally substituted by substituent groupF, or heterocyclic group optionally substituted by substituent group F,and

substituent group F; oxo, lower alkyl, hydroxy lower alkyl, amino, loweralkylamino, carbocycle lower alkyl, lower alkylcarbonyl, halogen,hydroxy, carboxy, lower alkylcarbonylamino, lower alkylcarbonyloxy,lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro)

Examples of further preferred embodiment of P^(R) include following b),k), l), and m).

—C(═O)—P^(R1),  b)

—CH₂—O—C(═O)—P^(R3),  l)

—CH₂—O—C(═O)—O—P^(R3),  n)

—CH(—CH₃)—O—C(═O)—O—P^(R3),  n)

(wherein each symbol is same as above)

Examples of another embodiment of a preferable substituent of P^(R)include groups of P-1 to P-83 in the following Tables 1 to 9.

TABLE 1

P-1 

P-2 

P-3 

P-4 

P-5 

P-6 

P-7 

P-8 

P-9 

P-10

TABLE 2

P-11

P-12

P-13

P-14

P-15

P-16

P-17

P-18

P-19

P-20

TABLE 3

P-21

P-22

P-23

P-24

P-25

P-26

P-27

P-28

P-29

P-30

TABLE 4

P-31

P-32

P-33

P-34

P-35

P-36

P-37

P-38

P-39

P-40

TABLE 5

P-41

P-42

P-43

P-44

P-45

P-46

P-47

P-48

P-49

P-50

TABLE 6

P-51

P-52

P-53

P-54

P-55

P-56

P-57

P-58

P-59

P-60

TABLE 7

  P-61

P-62

P-63

P-64

P-65

P-66

P-67

P-68

P-69

P-70

TABLE 8

  P-71

P-72

P-73

P-74

P-75

P-76

P-77

TABLE 9

  P-78

P-79

P-80

P-81

P-82

P-83

Examples of another embodiment of a particularly preferable substituentof P^(R) include following groups.

Examples of a preferable substituent in R^(1a) include hydrogen,halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionallysubstituted by substituent group C, lower alkenyl optionally substitutedby substituent group C, lower alkynyl optionally substituted bysubstituent group C, lower alkyloxy optionally substituted bysubstituent group C, lower alkenyloxy optionally substituted bysubstituent group C, lower alkylcarbonyl optionally substituted bysubstituent group C, lower alkyloxycarbonyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocyclecarbonyl optionally substituted bysubstituent group C, carbocycleoxy optionally substituted by substituentgroup C, carbocycleoxycarbonyl optionally substituted by substituentgroup C, heterocyclic group optionally substituted by substituent groupC, heterocycle lower alkyl optionally substituted by substituent groupC, heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Z—N(R^(A1))(R^(A2)),

—Z—N(R^(A3))—SO₂—(R^(A4)),

—Z—C(═O)—N(R^(A5))—SO₂—(R^(A6)),

—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R¹⁰,

—Z—S(═O)—R^(A11),

—Z—N(R^(A12))—C(═O)—O—R^(A13),

—Z—N(R^(A14))—C(═O)—N(R^(A15))(R^(A16)),

—Z—C(═O)—N(R^(A17))—C(═O)—N(R^(A18))(R^(A19)),

—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21) or

—Z—B(—OR^(A22))(—OR^(A23))

(substituent group C, R^(A1), R^(A2), R^(A3), R^(A5), R^(A7), R^(A9),R^(A10), R^(A11), R^(A12), R^(A13), R^(A14), R^(A15), R^(A16), R^(A17),R^(A18), R^(A19), R^(A20), R^(A21), R^(A22), R^(A23), and Z are same asthose of item 1).

Examples of a more preferable substituent in R^(1a) include hydrogen,halogen, hydroxy, carboxy, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkyloxy optionally substituted by substituent group C,lower alkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,

—Z—N(R^(A1))(R^(A2)),

—Z—N(R^(A7))—C(═O)—R^(A8),

—Z—N(R^(A12))—C(═O)—O—R^(A13), or

—Z—B(—OR^(A22))(—OR^(A23))

(substituent group C, R^(A1), R^(A2), R^(A7), R^(A8), R^(A12), R^(A13),R^(A22), R^(A23), and Z are same as those of item 1).

Examples of a preferable substituent in R^(1a) include hydrogen,halogen, hydroxy, carboxy, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkyloxy optionally substituted by substituent group C,lower alkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C, or

—Z—N(R1)(R^(A2))

(substituent group C, R^(A1), R^(A2), and Z are same as those of item1).

Examples of another embodiment of a preferable substituent in R^(1a)include hydrogen, carboxy, hydroxymethyl, methoxy, chlorine atom,bromine atom, ethoxymethyl, dimethylamino, hydroxy, —C(═O)—NH—S(═O)₂-Me,amino, methylamino, methylaminomethyl, —NH—C(═O)—CF₃, pyrazolyl,—NH—C(═O)-Me, —C(═O)N-Me₂, tetrazolyl, —NH—C(═O)-Ph, —C(═O)NH-Me,—C(═O)NH-Et, —C(═O)NH-cyclopropyl, methoxycarbonyl, methyl, propenyl,propyl, isopropyl, fluoromethyl, difluoromethyl, cyano, —C(═O)-Me,—CH(—OH)-Me, —B(—OH)₂,

(Me represents a methyl group, Ph represents a phenyl group, and Etrepresents an ethyl group) etc.

Examples of another embodiment of a more preferable substituent inR^(1a) include hydrogen, carboxy, hydroxymethyl, methoxy, bromine atom,ethoxymethyl, dimethylamino, hydroxy, —C(═O)—NH—S(═O)₂-Me, amino,methylamino, methyl, propenyl, —C(═O)-Me, —B(—OH)₂

(Me represents a methyl group) etc.

Examples of another embodiment of a further preferable substituent inR^(1a) include hydrogen, carboxy, and —C(═O)-Me.

Examples of a most preferable substituent in R^(1a) include hydrogen.

Examples of a preferable substituent in R_(2a) is hydrogen, halogen,carboxy, cyano, formyl, lower alkyl optionally substituted bysubstituent group C, lower alkenyl optionally substituted by substituentgroup C, lower alkynyl optionally substituted by substituent group C,lower alkyloxy optionally substituted by substituent group C, loweralkenyloxy optionally substituted by substituent group C, loweralkylcarbonyl optionally substituted by substituent group C, loweralkyloxycarbonyl optionally substituted by substituent group C,carbocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,carbocyclecarbonyl optionally substituted by substituent group C,carbocycleoxy optionally substituted by substituent group C,carbocycleoxycarbonyl optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C,heterocyclecarbonyl optionally substituted by substituent group C,heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Z—N(R^(B1))—SO₂—R^(B2),

—Z—N(R^(B3))—C(═O)—R^(B4),

—Z—N(R^(B5))—C(═O)—O—R^(B6),

—Z—C(═O)—N(R^(B7))(R^(B8)),

—Z—N(R^(B9))(R^(B10)), or

—Z—SO₂—R^(B11)

(substituent group C, R^(B1), R^(B2), R^(B3), R^(B4), R^(B5), R^(B6),R^(B7), R^(B8), R^(B9), R^(B10), R^(B11), and Z are same as those ofitem 1).

Examples of a more preferable substituent in R^(2a) is hydrogen, loweralkyl optionally substituted by substituent group C, carbocycle loweralkyl optionally substituted by substituent group C, heterocycle loweralkyl optionally substituted by substituent group C, or

—Z—N(R^(B9))(R^(B1))

(substituent group C, R^(B9), R^(B10), and Z are same as those of item1).

Examples of a further preferable substituent in R^(2a) include hydrogen,or lower alkyl optionally substituted by substituent group C,heterocycle lower alkyl optionally substituted by substituent group C

(substituent group C is same as that of item 1).

Examples of another embodiment of a preferable substituent in R^(2a)include hydrogen, hydroxymethyl, amino, methoxymethyl,methoxymethylcyclopropylmethyloxymethyl, cyanomethyl, aminomethyl,propyloxymethyl, —CH₂—NH—C(═O)-Me, methylaminomethyl, imidazolyl,dimethylaminomethyl, pyrrolidinyl, fluoromethyl, —CH₂—NH—C(═O)H

(Me represents a methyl group) etc.

Examples of another embodiment of a more preferable substituent inR^(2a) include hydrogen, hydroxymethyl,methoxymethylcyclopropylmethyloxymethyl, aminomethyl, propyloxymethyl,etc.

Examples of another embodiment of a further preferable substituent inR^(2a) include hydrogen.

Examples of a preferable substituent in R^(3a) include

hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkynyl optionally substitutedby substituent group C, lower alkyloxy optionally substituted bysubstituent group C, lower alkenyloxy optionally substituted bysubstituent group C, lower alkylcarbonyl optionally substituted bysubstituent group C, lower alkyloxycarbonyl optionally substituted bysubstituent group C, carbocyclic group optionally substituted bysubstituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocycleoxy lower alkyl optionally substituted bysubstituent group C, carbocyclecarbonyl optionally substituted bysubstituent group C, carbocycleoxy optionally substituted by substituentgroup C, carbocycleoxycarbonyl optionally substituted by substituentgroup C, heterocyclic group optionally substituted by substituent groupC, heterocycle lower alkyl optionally substituted by substituent groupC, heterocycleoxy lower alkyl optionally substituted by substituentgroup C, heterocyclecarbonyl optionally substituted by substituent groupC, heterocycleoxy optionally substituted by substituent group C,heterocycleoxycarbonyl optionally substituted by substituent group C,

—Z—N(R^(C1))—SO₂—R^(C2),

—Z—N(R^(C3))—C(═O)—R^(C4),

—Z—N(R^(C5))—C(═O)—O—R^(C6),

—Z—C(═O)—N(R^(C7))(R^(C5)),

—Z—N(R_(C9))(R^(C10)), or

—Z—SO₂—R^(C11)

(substituent group C, R^(C1), R^(C2), R^(C3), R^(C4), R^(C5), R^(C6),R^(C7), R^(C8), R^(C9), R^(C10), R^(C11), and Z are same as those ofitem 1).

Examples of a more preferable substituent in R^(3a) is hydrogen, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy lower alkyl optionallysubstituted by substituent group C,

—Z—N(R^(C1))—SO₂—R^(C2),

—Z—N(R^(C3))—C(═O)—R^(C4),

—Z—N(R^(C5))—C(═O)—O—R^(C6),

—Z—C(═O)—N(R^(C7))(R^(C8)), or

—Z—N(R^(C9))(R^(C10))

(substituent group C, R^(C1), R^(C2), R^(C3), R^(C4), R^(C5), R^(C6),R^(C7), R^(C8), R^(C9), R^(C10), and Z are same as those of item 1).

Examples of a further preferable substituent in R^(3a) include hydrogen,lower alkyl optionally substituted by substituent group C, lower alkynyloptionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, or carbocycle lower alkyloptionally substituted by substituent group C

(substituent group C is same as that of item 1).

Examples of another embodiment of a preferable substituent in R^(3a)include hydrogen, ethoxyethyl, methyl, ethyl, propyl,2,4-difluorobenzyl, methoxyethyl, cyanomethyl, cyanoethyl,3-chloro-2-fluorobenzyl, 1-methoxypropyl, pyridylmethyl, isopropyl,tetrahydropyranylmethyl, cyclopropylmethyl, benzyl,methylisoxazolylmethyl, methyloxadiazolyl, isopropyloxyethyl,hydroxyethyl, 4-fluorobenzyl, cyclopropyl, ethoxycarbonylethyl,—CH(Me)CH₂OMe, carboxyethyl, —CH₂CH₂C(═O)—N(Me)₂,—CH₂CH₂N(Me)-S(═O)₂-Ph, —CH₂CH₂—N(Me)-S(═O)₂-Me, —CH₂CH₂—NHC(═O)-Ph,—CH(Me)-CH₂—OMe, —CH₂CH₂—NH—S(═O)₂-Ph, —CH₂CH₂—NH—C(═O)—O—CH(Me)₂,—CH₂CH₂—C(═O)—NH-Ph, —CH₂CH₂—N(Me)C(═O)-Ph, —CH₂CH₂—NH—C(═O)-Me,—CH₂CH₂—NH—S(═O)₂-Me, aminoethyl, —CH₂CH₂—N(Me)—C(═O)-Me,—CH₂CH₂—C(═O)—N(Me)-Ph, —CH₂CH₂—NH—C(═O)—O-tBu,piperidinylcarbonylethyl, dimethylaminoethyl, cyclopropylmethyl,methylaminoethyl, furanylmethyl, morpholinylcarbonylethyl, sec-butyl,pentan-2-yl, carboxypropyl, ethoxycarbonylpropyl, phenylpropyl,propyloxyethyl, aminopropyl, dimethylaminomethyl, dimethylaminoethyl,diethylaminomethyl, diethylaminoethyl, dimethylaminopropyl,methylaminocarbonylethyl, 1,1,1-trifluoropropan-2-yl, 1,1-difluoroethyl,1,1,1-trifluoroethyl, 1,1,1-trifluoropropyl, trifluoromethyloxyethyl,trifluoromethylcarbonylaminomethyl, methylsulfonylethyl,methylcarbonyloxyethyl, methylcarbonyloxypropyl, 1-fluoropropyl,fluorocyclopropyl, difluorocyclopropyl, 3,3-dimethylbutan-2-yl,1-fluoroethyl, 1-methoxypropan-2-yl, amino, thiazolylmethyl,methylsulfonylethyl, 4-fluorophenyloxyethyl, pyridyl, pentan-2-yl,butan-2-yl, 3-methylbuten-2-yl, as well as groups shown below

(Me represents a methyl group, Ph represents a phenyl group, and tBurepresents a tert-butyl group) etc.

Examples of another embodiment of a more preferable substituent inR^(3a) include ethoxyethyl, methyl, ethyl, 2,4-difluorobenzyl,methoxyethyl, cyanomethyl, 3-chloro-2-fluorobenzyl, methoxypropyl,pyridylmethyl, isopropyl, tetrahydropyranylmethyl, cyclopropylmethyl,benzyl, methylisoxazolylmethyl, 4-fluorobenzyl, cyclopropyl,ethoxycarbonylethyl, —CH(Me)CH₂OMe, carboxyethyl, —CH₂CH₂C(═O)—N(Me)₂,—CH₂CH₂N(Me)-S(═O)₂-Ph, —CH₂CH₂—N(Me)-S(═O)₂-Me, —CH₂CH₂—NHC(═O)-Ph,—CH(Me)-CH₂—OMe, —CH₂CH₂—NH—S(═O)₂-Ph, —CH₂CH₂—NH—C(═O)—O—CH(Me)₂,—CH₂CH₂—C(═O)—NH-Ph, —CH₂CH₂—N(Me)C(═O)-Ph, —CH₂CH₂—NH—C(═O)-Me,—CH₂CH₂—NH—S(═O)₂-Me, aminoethyl, 1,1,1-trifluoropropan-2-yl, propyl,methylthiomethyl, hydrogen, fluorocyclopropyl, trifluoromethoxyethyl,1-fluoropropyl, 1-fluoroethyl, methylcarbonyloxymethyl,1,1-difluoromethyl, and groups shown below

(Me represents methyl group, and Ph represents phenyl group) etc.

Examples of another embodiment of a further preferable substituent inR^(3a) include ethoxyethyl, methyl, ethyl, 2,4-difluorobenzyl,methoxyethyl, cyanomethyl, 3-chloro-2-fluorobenzyl, methoxypropyl,pyridylmethyl, isopropyl, tetrahydropyranylmethyl, cyclopropylmethyl,benzyl, 4-fluorobenzyl, cyclopropyl, ethoxycarbonylethyl, —CH(Me)CH₂OMe,carboxyethyl, 1,1,1-trifluoropropan-2-yl, hydroxyethyl, 1-fluoroethyl

(Me represents methyl group) etc.

Examples of another embodiment of a most preferable substituent inR^(3a) include 1,1,1-trifluoropropan-2-yl.

Examples of a preferable substituent in R^(5a), R^(6a), R^(7a), R^(8a),R^(9a), R^(10a), and R^(11a) include hydrogen, carboxy, cyano, loweralkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocycleoxy lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, heterocycle lower alkyl optionallysubstituted by substituent group C, heterocycleoxy lower alkyloptionally substituted by substituent group C, heterocyclecarbonyloptionally substituted by substituent group C, heterocycleoxycarbonyloptionally substituted by substituent group C,

—Y—S—R^(D1),

—Z—S(═O)—R^(D2),

—Z—SO₂—R^(D3),

—C(═O)—C(═O)—R^(D4),

—C(═O)—N(R^(D5))(R^(D6)),

—Z—C(R^(D7))(R^(D8))(R^(D9)), or

—Z—CH₂—R^(D10)

(substituent group C, R^(D1), R^(D2), R^(D3), R^(D4), R^(D5), R^(D6),R^(D7), R^(D8), R^(D9), R^(D10), and Z are same as those of item 1).

Examples of a more preferable substituent in R^(5a), R^(6a), R^(7a),R^(8a), R^(9a), R^(10a), and R^(11a) include hydrogen, lower alkyloptionally substituted by substituent group C, carbocyclic groupoptionally substituted by substituent group C, carbocycleoxy lower alkyloptionally substituted by substituent group C, heterocyclic groupoptionally substituted by substituent group C, tricyclic condensedheterocyclic group optionally substituted by substituent group C,heterocycleoxy lower alkyl optionally substituted by substituent groupC,

—Y—S—R^(D1), or

—Z—C(R^(D7))(R^(D8))(R^(D9))

(substituent group C, R^(D1), R^(D7), R^(D8), R^(D9), Y, and Z are sameas those of item 1).

Examples of another embodiment of a preferable substituent in R^(5a),R^(6a), R^(7a), R^(8a), R^(9a), R^(10a), and R^(11a) include hydrogen,benzhydryl, benzyl, indolylmethyl, cyclohexylmethyl, phenethyl,benzylthiomethyl, 3,5-dimethylisoxazolyl,5-chloro-3-ethylbenzothiophenyl, 4-fluorobenzyl, methylthiazolylmethyl,cyclopentylmethyl, 4-methoxybenzyl, 3-fluorobenzyl, naphthylmethyl,methyl, 3-trifluoromethylbenzyl, pyridylmethyl,4-methylcarbonylaminobenzyl, pyrimidinyl, isobutyl, phenoxyethyl,methoxypropyl, phenylpropyl, as well as tricyclic or tetracycliccondensed heterocyclic group optionally substituted by substituent groupC such as the following groups

(wherein R^(E6) represents a group selected from substituent group C,and m of R^(E6)s may be the same or different) etc.

Examples of another embodiment of a more preferable substituent inR^(5a), R^(6a), R^(7a), R^(8a), R^(9a), R^(10a), and R^(11a) includehydrogen, benzhydryl, benzyl, indolylmethyl, cyclohexylmethyl,phenethyl, 3,5-dimethylisoxazolyl, 5-chloro-3-ethylbenzothiophenyl,biphenylmethyl, 4-fluorobenzyl, methylthiazolylmethyl, cyclopenylmethyl,4-methoxybenzyl, 3-fluorobenzyl, naphthylmethyl, methyl,3-trifluoromethylbenzyl, pyridylmethyl, 4-methylcarbonylaminobenzyl,pyrimidinyl, and the following groups

(wherein R^(E6) represents a group selected from substituent group C,and m of R^(E6)s may be the same or different), etc.

, etc.

1) Examples of a preferable embodiment when B is CR^(5a)R^(6a), and B²is NR^(7a) include

the case where R^(3a) and R^(7a) are taken together with an adjacentatom to form a heterocycle optionally substituted by substituent groupD.

2) Examples of a preferable embodiment when B is NR^(7a), and B² isCR^(5a)R^(6a) include

the case where R^(3a) and R^(6a) are taken together with an adjacentatom to form a heterocycle optionally substituted by substituent groupD.

3) Examples of a preferable embodiment when B is CR⁸R^(9a), and B² isCR^(10a)R^(11a) include

the case where R^(8a) and R^(10a) are taken together with an adjacentatom to form a carbocycle or a heterocycle optionally substituted bysubstituent group D.

4) Examples of another preferable embodiment when B¹ is CR^(8a)R^(9a),and B² is CR^(10a)R^(11a) include

the case where R^(3a) and R^(11a) are taken together with an adjacentatom to form a heterocycle optionally substituted by substituent groupD.

When one of B and B² is CR^(5a)R^(6a) and the other is NR^(7a),

the case where B is NR^(7a) and B² is CR^(5a)R^(6a) is more preferable.

When one of B and B² is CR^(5a)R^(6a) and the other is NR^(7a),

it is preferable that at least one of R^(5a) or R^(6a) is hydrogen. Amore preferable embodiment is such that R^(5a) is hydrogen and R^(6a) ishydrogen. In this case, R^(7a) is not a hydrogen atom.

A particularly preferable embodiment of B¹ and B² is such that B isNR^(7a) and B² is CR^(5a)R^(6a).

A most preferable embodiment of B and B² is such that B is NR^(7a) andB² is CH₂.

A preferable embodiment of R^(7a) is carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, and heterocycle lower alkyloptionally substituted by substituent group C.

A more preferable embodiment of R^(7a) is cycloalkyl, cycloalkenyl,aryl, non-aromatic condensed carbocyclic group, heteroaryl, non-aromaticheterocyclic group, bicyclic condensed heterocyclic group, tricycliccondensed heterocyclic group, lower alkyl substituted by one or twocarbocyclic groups, and lower alkyl substituted by one or twoheterocyclic groups.

A further preferable embodiment of R^(7a) is benzyl, benzhydryl,4-fluorobenzyl, p-methoxybenzyl, and the following groups

(wherein R^(E6), and m are same as those of item 1).

A particularly preferable embodiment of R^(7a) is the following groups

(wherein R^(E6), and m are same as those of item 1).

A most preferable embodiment of R^(7a) is the following groups

(wherein R^(E6), and m are same as those of item 1).

When B is CR^(8a)R^(9a), and B² is CR^(10a)R^(11a), it is preferablethat R^(9a) and R^(11a) are hydrogen. A preferable embodiment of R^(8a)and R^(10a) is such that any one of them is hydrogen.

When R^(9a) and R^(11a) are hydrogen, and any one of R^(8a) and R^(10a)is hydrogen, a preferable embodiment of the other of R^(8a) and R^(10a)is the following groups

—Z—C(R^(E1))(R^(E2))(R^(E3))

or

(wherein Z, R^(E1), R^(E2), R^(E3), R^(E6), and m are same as those ofitem 1).

When R^(9a) and R^(11a) are hydrogen, and any one of R^(8a) and R^(10a)is hydrogen, a further preferable embodiment of the other of R^(8a) andR^(10a) is the following groups

(wherein R^(E6), and m are same as those of item 1).

When R^(9a) and R^(11a) are hydrogen, and any one of R^(8a) and R^(10a)is hydrogen, a most preferable embodiment of the other of R^(8a) andR^(10a) is the following groups

(wherein R^(E6), and m are same as those of item 1).

Examples of a preferable substituent in substituent group D includecarbocyclic group optionally substituted by substituent group C,heterocyclic group optionally substituted by substituent group C,carbocycle lower alkyl optionally substituted by substituent group C,and heterocycle lower alkyl optionally substituted by substituent groupC.

Examples of another embodiment of a preferable substituent insubstituent group D include benzyl, benzhydryl, 4-fluorobenzyl,p-methoxybenzyl,

(wherein R^(E6) represents a group selected from substituent group C,and m of R^(E6)s may be the same or different) etc.

Examples of a preferable substituent of R^(E6) include halogen, cyano,hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, lower alkynyl,halogeno lower alkyl, lower alkyloxy, lower alkyl amino, halogeno loweralkyloxy, carbocyclic group, etc.

Examples of a more preferable substituent of R^(E6) include fluorineatom, chlorine atom, bromine atom, cyano, hydroxy, methyl, ethyl,ethynyl, hydroxymethyl, isopropyl, methoxy, ethoxy, methoxymethyl,cyclopropyl, dimethylamino, trifluoromethyl, oxo, carboxy, etc.

Examples of a particularly preferable substituent of R^(E6) includefluorine atom, chlorine atom, bromine atom, methyl, methoxy, andtrifluoromethyl.

A preferable embodiment of m is an integer of 0 to 6, further preferablyan integer of 0 to 3, and most preferably an integer of 0 to 2.

One of characteristics of the compound in the present invention is inthat a prodrug of a polycyclic carbamoylpyridone derivative, in whichtwo or more rings are condensed, such as shown in the formula (I) initem 1 and/or a composition including them, has high inhibitory activityon cap-dependent endonuclease, and has an effect of treating and/orpreventing influenza infectious disease.

The characteristic of the compound in the present invention is thatcap-dependent endonuclease inhibitory activity was improved, by applyinga functional group as shown below to R^(1a) in the formula (I).

Functional group: hydrogen, halogen, hydroxy, carboxy, cyano, formyl,lower alkyl optionally substituted by substituent group C, lower alkenyloptionally substituted by substituent group C, lower alkynyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkenyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, carbocyclic group optionallysubstituted by substituent group C, carbocycle lower alkyl optionallysubstituted by substituent group C, carbocyclecarbonyl optionallysubstituted by substituent group C, carbocycleoxy optionally substitutedby substituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocyclecarbonyl optionally substituted bysubstituent group C, heterocycleoxy optionally substituted bysubstituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C,

—Z—N(R^(A1))(R^(A2))

—Z—Z—(R^(A3))—SO₂—(R^(A4)),

—Z—C(═O)—N(R^(A5))—SO₂—(R^(A6)),

—Z—N(R^(A1))—C(═O)—R^(A8),

—Z—S—R^(A9),

—Z—SO₂—R^(A10),

—Z—S(═O)—R¹¹,

—Z—N(R^(A12))—C(═O)—O—R^(A13),

—Z—N(R^(A14))—C(═O)—N(R^(A15))(R^(A16)),

—Z—C(═O)—N(R^(A17))—C(═O)—N(R^(A18))(R^(A19)), or

—Z—N(R^(A20))—C(═O)—C(═O)—R^(A21)

(substituent group C, R^(A1), R^(A2), R^(A3), R^(A5), R^(A7), R^(A8),R^(A9), R^(A12), R^(A13), R^(A14), R^(A15), R^(A16), R^(A17), R^(A18),R^(A19), R^(A20), and R^(A21) are same as those of item 1)

The characteristic of a more preferable compound in the presentinvention is that cap-dependent endonuclease inhibitory activity wasimproved, by applying a functional group as shown below to R^(1a) in theformula (I).

Functional group: hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C,

—Z—N(R)(R^(A2)),

—Z—N(R^(A7))—C(═O)—R^(A8), or

—Z—N(R^(A12))—C(═O)—O—R^(A13)

(substituent group C, R^(A1), R^(A2), R^(A7), R^(A8), R^(A12), R^(A13),and Z are same as those of item 1).

The characteristic of a further preferable compound in the presentinvention is that cap-dependent endonuclease inhibitory activity wasimproved, by applying a functional group as shown below to R^(1a) in theformula (I).

Functional group: hydrogen, halogen, hydroxy, carboxy, lower alkyloptionally substituted by substituent group C, lower alkenyl optionallysubstituted by substituent group C, lower alkyloxy optionallysubstituted by substituent group C, lower alkylcarbonyl optionallysubstituted by substituent group C, lower alkyloxycarbonyl optionallysubstituted by substituent group C, heterocyclic group optionallysubstituted by substituent group C, or

—Z—N(R^(A1))(R^(A2))

(substituent group C, R^(A1), R^(A2), and Z are same as those of item1).

The characteristic of a particularly preferable compound in the presentinvention is that cap-dependent endonuclease inhibitory activity wasimproved, by applying a functional group as shown below to R^(1a) in theformula (I).

Functional group: hydrogen, acetyl, or carboxy

Another characteristic of the compound in the present invention is thatcap-dependent endonuclease inhibitory activity was improved, byintroducing one, two or more of lipid-soluble functional groups shownbelow on carbon atom or on nitrogen atom of B¹ and/or B² in the formula(I).

Lipid-soluble functional group: carbocyclic group optionally substitutedby substituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocycleoxy lower alkyl optionally substituted bysubstituent group C, carbocycleoxycarbonyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C, heterocycleoxy lower alkyl optionally substitutedby substituent group C, heterocycleoxycarbonyl optionally substituted bysubstituent group C

(substituent group C is same as that of item 1).

Another characteristic of a more preferable compound in the presentinvention is that cap-dependent endonuclease inhibitory activity isimproved, by introducing one lipid-soluble functional group shown belowon carbon atom or on nitrogen atom of B or B² in the formula (I).

Lipid-soluble functional group: carbocyclic group optionally substitutedby substituent group C, carbocycle lower alkyl optionally substituted bysubstituent group C, carbocycleoxy lower alkyl optionally substituted bysubstituent group C, heterocyclic group optionally substituted bysubstituent group C, heterocycle lower alkyl optionally substituted bysubstituent group C

(substituent group C is same as that of item 1).

Another characteristic of a particularly preferable compound in thepresent invention is that cap-dependent endonuclease inhibitory activityis improved, by introducing one lipid-soluble functional group shownbelow on carbon atom or on nitrogen atom of B or B² in the formula (I).

Lipid-soluble functional group: carbocyclic group optionally substitutedby substituent group C, heterocyclic group optionally substituted bysubstituent group C (substituent group C is same as that of item 1).

Other characteristic of a preferable compound in the present inventionis that the compound is efficiently absorbed into the body after in vivoadministration (for example, oral administration) and shows high drugefficacy by introducing a group to form a prodrug into a P^(R) part inthe formula (I).

Other characteristic of a more preferable compound in the presentinvention is that the compound is efficiently absorbed into the bodyafter administration and shows high drug efficacy by introducing a groupselected from the following formulae a) to v) into a P^(R) part in theformula (I).

—C(═O)—P^(R0),  a)

—C(═O)—P^(R1),  b)

—C(═O)-L-O—P^(R1),  c)

—C(═O)-L-O-L-O—P^(R1),  d)

—C(═O)-L-O—C(═O)—P^(R1),  e)

—C(═O)—O—P^(R2),  f)

—C(═O)—N(P^(R2))₂,  g)

—(═O)—O-L-O—P^(R2),  h)

—CH₂—O—P^(R3),  i)

—CH₂—O-L-O—P^(R3),  j)

—CH₂—O—C(═O)—P^(R3),  k)

—CH₂—O—C(═O)—O—P^(R3),  l)

—CH(—CH₃)—O—C(═O)—O—P^(R3),  m)

—CH₂—O—C(═O)—N(—K)—P^(R3),  n)

—CH₂—O—C(═O)—O-L-O—P^(R3),  o)

—CH₂—O—C(═O)—O-L-N(P^(R3))₂,  p)

—CH₂—O—C(═O)—N(—K)-L-O—P^(R3),  q)

—CH₂—O—C(═O)—N(—K)-L-N(P)₂,  r)

—CH₂—O—C(═O)—O-L-O-L-O—P^(R3),  s)

—CH₂—O—P(═O)(—OH)₂,  t)

—CH₂—O—P(═O)(—OBn)₂,  u)

—CH₂—P^(R4)  v)

(wherein L is straight or branched lower alkylene,

K is hydrogen, or straight or branched lower alkylene,

P^(R0) is lower alkyl optionally substituted by substituent group F,

P^(R1) is carbocyclic group optionally substituted by substituent groupF, heterocyclic group optionally substituted by substituent group F,lower alkyl amino optionally substituted by substituent group F, orlower alkylthio optionally substituted by substituent group F,

P^(R2) is lower alkyl optionally substituted by substituent group F,carbocyclic group optionally substituted by substituent group F, orheterocyclic group optionally substituted by substituent group F,

P^(R3) is lower alkyl optionally substituted by substituent group F,carbocyclic group optionally substituted by substituent group F,heterocyclic group optionally substituted by substituent group F, loweralkyl amino optionally substituted by substituent group F, carbocyclelower alkyl optionally substituted by substituent group F, heterocyclelower alkyl optionally substituted by substituent group F, or loweralkylsilyl,

P^(R4) is carbocyclic group optionally substituted by substituent groupF, or heterocyclic group optionally substituted by substituent group F.

Substituent group F; oxo, lower alkyl, hydroxyl lower alkyl, amino,lower alkylamino, carbocycle lower alkyl, lower alkylcarbonyl, halogen,hydroxy, carboxy, lower alkylcarbonylamino, lower alkylcarbonyloxy,lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro)

Other characteristic of a more preferable compound in the presentinvention is that the compound is efficiently absorbed into the bodyafter administration and shows high drug efficacy by introducing groupsof P-1 to P-77 in Tables 1 to 8 into a P^(R) part in the formula (I).

A preferable embodiment of the present invention will be exemplifiedbelow. In the formula (III), the formula (III′), the formula (III″), theformula (III′″), the formula (III″″), the formula (III′″″):

1)

a compound in which R^(1a) is hydrogen (hereinafter, R^(1a) is R1-1),

a compound in which R^(1a) is carboxy (hereinafter, R^(1a) is R1-2),

a compound in which R^(1a) is halogen (hereinafter R^(1a) is R1-3),

a compound in which R^(1a) is hydroxy (hereinafter, R^(1a) is R1-4),

a compound in which R^(1a) is lower alkyl optionally substituted bysubstituent group C (hereinafter, R^(1a) is R1-5),

a compound in which R^(1a) is lower alkylcarbonyl optionally substitutedby substituent group C (hereinafter, R^(1a) is R1-6),

a compound in which R^(1a) is lower alkyloxycarbonyl optionallysubstituted by substituent group C (hereinafter, R^(1a) is R1-7),

a compound in which R^(1a) is amino (hereinafter, R^(1a) is R1-8),

2)

a compound in which R^(2a) is hydrogen (hereinafter, R^(2a) is R2-1),

a compound in which R^(2a) is lower alkyl optionally substituted bysubstituent group C (hereinafter, R^(2a) is R2-2),

3)

a compound in which R^(3a) is lower alkyl optionally substituted bysubstituent group C (hereinafter, R^(3a) is R3-1),

a compound in which R^(3a) is carbocycle lower alkyl optionallysubstituted by substituent group C (hereinafter, R^(3a) is R3-2),

a compound in which R^(3a) is heterocycle lower alkyl optionallysubstituted by substituent group C (hereinafter, R^(3a) is R3-3),

a compound in which R^(3a) is carbocyclic group optionally substitutedby substituent group C (hereinafter, R^(3a) is R3-4),

a compound in which R^(3a) is heterocyclic group optionally substitutedby substituent group C (hereinafter, R^(3a) is R3-5),

4)

a compound in which P^(R) is —C(═O)P^(R1) (hereinafter, P^(R) is Pr-1),

a compound in which P^(R) is —CH₂—O—C(═O)—P^(R3) (hereinafter, P^(R) isPr-2),

a compound in which P^(R) is —CH₂—O—C(═O)—O—P^(R) (hereinafter, P^(R) isPr-3),

a compound in which P^(R) is —CH(—CH₃)—O—C(═O)—O—P^(R) (hereinafter,P^(R) is Pr-4),

(wherein each symbol is same as above)

in the formula (III′),

a compound in which R^(7a) is carbocyclic group optionally substitutedby

substituent group C, and R^(5a) and R^(6a) are hydrogen (hereinafter,R7-1),

a compound in which R^(7a) is heterocyclic group optionally substitutedby substituent group C, and R^(5a) and R^(6a) are hydrogen (hereinafter,R7-2),

a compound in which R^(7a) is carbocycle lower alkyl optionallysubstituted by substituent group C, and R^(5a) and R^(6a) are hydrogen(hereinafter, R7-3),

in the formula (III),

a compound in which R^(9a) is carbocyclic group optionally substitutedby substituent group C, and R^(8a), R^(10a) and R^(11a) are hydrogen(hereinafter, R9-1),

a compound in which R^(9a) is heterocyclic group optionally substitutedby substituent group C, and R^(8a), R^(10a), and R^(11a) are hydrogen(hereinafter, R9-2),

a compound in which R^(9a) is carbocycle lower alkyl optionallysubstituted by substituent group C, and R^(8a), R^(10a), and R^(11a) arehydrogen (hereinafter, R9-3)

Herein, the substituent group C is at least one selected from asubstituent group consisting of halogen, cyano, hydroxy, carboxy,formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, loweralkyloxy, carbocyclic group, heterocyclic group, carbocycle loweralkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, loweralkyloxy lower alkyl, lower alkyloxy lower alkyloxy, loweralkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, loweralkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, andlower alkylsulfonylamino.

Compounds in which, in the formula (III′), a combination of R^(1a),R^(2a), R^(3a), P^(R), as well as (R^(5a), R^(6a), and R^(7a)) is asfollows.

(R1-1, R2-1, R3-1, Pr-1, R7-1), (R1-1, R2-1, R3-1, Pr-1, R7-2), (R1-1,R2-1, R3-1, Pr-1, R7-3), (R1-1, R2-1, R3-1, Pr-2, R7-1), ((R-1, R2-1,R3-1, Pr-2, R7-2), (R1-1, R2-1, R3-1, Pr-2, R7-3), (R1-1, R2-1, R3-1,Pr-3, R7-1), (R1-1, R2-1, R3-1, Pr-3, R7-2), (R3-1, R2-1, R3-1, Pr-3,R7-3), (R-1, R2-1, R3-1, Pr-4, R7-1), (R1-1, R2-1, R3-1, Pr-4, R7-2),(R1-1, R2-1, R3-1, Pr-4, R7-3), (R1-1, R2-1, R3-2, Pr-1, R7-1), (R1-1,R2-1, R3-2, Pr-4, R7-2), (R1-1, R2-1, R3-2, Pr-4, R7-3), (R1-1, R2-1,R3-2, Pr-2, R7-1), (R1-1, R2-1, R3-2, Pr-2, R7-2), (R1-1, R2-1, R3-2,Pr-2, R7-3), (R1-1, R2-1, R3-2, Pr-3, R7-1), (R1-1, R2-1, R3-2, Pr-3,R7-2), (R1-1, R2-1, R3-2, Pr-3, R7-3), (R1-1, R2-1, R3-2, Pr-4, R7-1),(R-1, R2-1, R3-2, Pr-4, R7-2), (R1-1, R2-1, R3-2, Pr-4, R7-3), (R1-1,R2-1, R3-3, Pr-1, R7-1), (R1-1, R2-1, R3-3, Pr-1, R7-2), (R1-1, R2-1,R3-3, Pr-1, R7-3), (R1-1, R2-1, R3-3, Pr-2, R7-1), (R1-1, R2-1, R3-3,Pr-2, R7-2), (R1-1, R2-1, R3-3, Pr-2, R7-3), (R1-1, R2-1, R3-3, Pr-3,R7-1), (R1-1, R2-1, R3-3, Pr-3, R7-2), (R1-1, R2-1, R3-3, Pr-3, R7-3),(R1-1, R2-1, R3-3, Pr-4, R7-1), (R1-1, R2-1, R3-3, Pr-4, R7-2), (R1-1,R2-1, R3-3, Pr-4, R7-3), (R1-1, R2-1, R3-4, Pr-1, R7-1), (R1-1, R2-1,R3-4, Pr-1, R7-2), (R-1, R2-1, R3-4, Pr-1, R7-3), (R1-1, R2-1, R3-4,Pr-2, R7-1), (R1-1, R2-1, R3-4, Pr-2, R7-2), (R1-1, R2-1, R3-4, Pr-2,R7-3), (R1-1, R2-1, R3-4, Pr-3, R3-4, Pr-4, R7-1), (R1-1, R2-1, R3-4,Pr-4, R7-2), (R1-1, R2-1, R3-4, Pr-4, R7-3), (R1-1, R2-1, R3-5, Pr-1,R7-1), (R1-1, R2-1, R3-5, Pr-1, R7-2), (R1-1, R2-1, R3-5, Pr-1, R7-3),(R1-1, R2-1, R3-5, Pr-2, R7-1), ((R-1, R2-1, R3-5, Pr-2, R7-2), (R1-1,R2-1, R3-5, Pr-2, R7-3), (R1-1, R2-1, R3-5, Pr-3, R7-1), (R1-1, R2-1,R3-5, Pr-3, R7-2), (R1-1, R2-1, R3-5, Pr-3, R7-3), (R1-1, R2-1, R3-5,Pr-4, R7-1), (R1-1, R2-1, R3-5, Pr-4, R7-2), (R-1, R2-1, R3-5, Pr-4,R7-3), (R1-1, R2-2, R3-1, Pr-1, R7-1), (R1-1, R2-2, R3-1, Pr-1, R7-2),(R1-1, R2-2, R3-1, Pr-1, R7-3), (R1-1, R2-2, R3-1, Pr-2, R7-1), (R1-1,R2-2, R3-1, Pr-2, R7-2), (R1-1, R2-2, R3-1, Pr-2, R7-3), (R1-1, R2-2,R3-1, Pr-3, R7-1), ((R-1, R2-2, R3-1, Pr-3, R7-2), ((R-1, R2-2, R3-1,Pr-3, R7-3), (R1-1, R2-2, R3-1, Pr-4, R7-1), (R1-1, R2-2, R3-1, Pr-4,R7-2), (R1-1, R2-2, R3-1, Pr-4, R7-3), (R1-1, R2-2, R3-2, Pr-1, R7-1),(R1-1, R2-2, R3-2, Pr-1, R7-2), (R1-1, R2-2, R3-2, Pr-1, R7-3), (R-1,R2-2, R3-2, Pr-2, R7-1), (R3-1, R2-2, R3-2, Pr-2, R7-2), (R1-1, R2-2,R3-2, Pr-2, R7-3), (R1-1, R2-2, R3-2, Pr-3, R7-1), (R1-1, R2-2, R3-2,Pr-3, R7-2), (R1-1, R2-2, R3-2, Pr-3, R7-3), (R1-1, R2-2, R3-2, Pr-4,R7-1), (R1-1, R2-2, R3-2, Pr-4, R7-2), (R1-1, R2-2, R3-2, Pr-4, R7-3),(R1-1, R2-2, R3-3, Pr-1, R7-1), (R1-1, R2-2, R3-3, Pr-1, R7-2), (R1-1,R2-2, R3-3, Pr-1, R7-3), (R1-1, R2-2, R3-3, Pr-2, R7-1), (R1-1, R2-2,R3-3, Pr-2, R7-2), (R1-1, R2-2, R3-3, Pr-2, R7-3), (R1-1, R2-2, R3-3,Pr-3, R7-1), (R1-1, R2-2, R3-3, Pr-3, R7-2), (R1-1, R2-2, R3-3, Pr-3,R7-3), (R1-1, R2-2, R3-3, Pr-4, R7-1), (R1-1, R2-2, R3-3, Pr-4, R7-2),(R1-1, R2-2, R3-3, Pr-4, R7-3), (R1-1, R2-2, R3-4, Pr-1, R7-1), (R1-1,R2-2, R3-4, Pr-1, R7-2), (R1-1, R2-2, R3-4, Pr-1, R7-3), (R1-1, R2-2,R3-4, Pr-2, R7-1), (R1-1, R2-2, R3-4, Pr-2, R7-2), (R1-1, R2-2, R3-4,Pr-2, R7-3), (R1-1, R2-2, R3-4, Pr-3, R7-1), (R1-1, R2-2, R3-4, Pr-3,R7-2), (R1-1, R2-2, R3-4, Pr-3, R7-3), (R1-1, R2-2, R3-4, Pr-4, R7-1),(R1-1, R2-2, R3-4, Pr-4, R7-2), (R1-1, R2-2, R3-4, Pr-4, R7-3), (R1-1,R2-2, R3-5, Pr-1, R7-1), (R1-1, R2-2, R3-5, Pr-1, R7-2), (R1-1, R2-2,R3-5, Pr-1, R7-3), (R1-1, R2-2, R3-5, Pr-2, R7-1), (R1-1, R2-2, R3-5,Pr-2, R7-2), (R1-1, R2-2, R3-5, Pr-2, R7-3), (R1-1, R2-2, R3-5, Pr-3,R7-1), (R1-1, R2-2, R3-5, Pr-3, R7-2), (R1-1, R2-2, R3-5, Pr-3, R7-3),(R1-1, R2-2, R3-5, Pr-4, R7-1), (R1-1, R2-2, R3-5, Pr-4, R7-2), (R1-1,R2-2, R3-5, Pr-4, R7-3),

(R1-2, R2-1, R3-1, Pr-1, R7-1), (R1-2, R2-1, R3-1, Pr-1, R7-2), (R1-2,R2-1, R3-1, Pr-1, R7-3), (R1-2, R2-1, R3-1, Pr-2, R7-1), (R1-2, R2-1,R3-1, Pr-2, R7-2), (R1-2, R2-1, R3-1, Pr-2, R7-3), (R1-2, R2-1, R3-1,Pr-3, R7-1), (R1-2, R2-1, R3-1, Pr-3, R7- 2), (R1-2, R2-1, R3-1, Pr-3,R7-3), (R1-2, R2-1, R3-1, Pr-4, R7-1), (R1-2, R2-1, R3-1, Pr-4, R7-2),(R1-2, R2-1, R3-1, Pr-4, R7-3), (R1-2, R2-1, R3-2, Pr-1, R7-1), (R1-2,R2-1, R3-2, Pr-1, R7-2), (R1-2, R2-1, R3-2, Pr-1, R7-3), (R1-2, R2-1,R3-2, Pr-2, R7-1), (R1-2, R2-1, R3-2, Pr-2, R7-2), (R1-2, R2-1, R3-2,Pr-2, R7-3), (R1-2, R2-1, R3-2, Pr-3, R7-1), (R1-2, R2-1, R3-2, Pr-3,R7-2), (R1-2, R2-1, R3-2, Pr-3, R7-3), (R1-2, R2-1, R3-2, Pr-4, R7-1),(R1-2, R2-1, R3-2, Pr-4, R7-2), (R1-2, R2-1, R3-2, Pr-4, R7-3), (R1-2,R2-1, R3-3, Pr-1, R7-1), (R1-2, R2-1, R3-3, Pr-1, R7-2), (R1-2, R2-1,R3-3, Pr-1, R7-3), (R1-2, R2-1, R3-3, Pr-2, R7-1), (R1-2, R2-1, R3-3,Pr-2, R7-2), (R1-2, R2-1, R3-3, Pr-2, R7-3), (R1-2, R2-1, R3-3, Pr-3,R7-1), (R1-2, R2-1, R3-3, Pr-3, R7-2), (R1-2, R2-1, R3-3, Pr-3, R7-3),(R1-2, R2-1, R3-3, Pr-4, R7-1), (R1-2, R2-1, R3-3, Pr-4, R7-2), (R1-2,R2-1, R3-3, Pr-4, R7-3), (R1-2, R2-1, R3-4, Pr-1, R7-1), (R1-2, R2-1,R3-4, Pr-1, R7-2), (R1-2, R2-1, R3-4, Pr-1, R7-3), (R1-2, R2-1, R3-4,Pr-2, R7-1), (R1-2, R2-1, R3-4, Pr-2, R7-2), (R1-2, R2-1, R3-4, Pr-2,R7-3), (R1-2, R2-1, R3-4, Pr-3, R7-1), (R1-2, R2-1, R3-4, Pr-3, R7-2),(R1-2, R2-1, R3-4, Pr-3, R7-3), (R1-2, R2-1, R3-4, Pr-4, R7-1), (R1-2,R2-1, R3-4, Pr-4, R7-2), (R1-2, R2-1, R3-4, Pr-4, R7-3), (R1-2, R2-1,R3-5, Pr-1, R7-1), (R1-2, R2-1, R3-5, Pr-1, R7-2), (R1-2, R2-1, R3-5,Pr-1, R7-3), (R1-2, R2-1, R3-5, Pr-2, R7-1), (R1-2, R2-1, R3-5, Pr-2,R7-2), (R1-2, R2-1, R3-5, Pr-2, R7-3), (R1-2, R2-1, R3-5, Pr-3, R7-1),(R1-2, R2-1, R3-5, Pr-3, R7-2), (R1-2, R2-1, R3-5, Pr-3, R7-3), (R1-2,R2-1, R3-5, Pr-4, R7-1), (R1-2, R2-1, R3-5, Pr-4, R7-2), (R1-2, R2-1,R3-5, Pr-4, R7-3), (R1-2, R2-2, R3-1, Pr-1, R7-1), (R1-2, R2-2, R3-1,Pr-1, R7-2), (R1-2, R2-2, R3-1, Pr-1, R7-3), (R1-2, R2-2, R3-1, Pr-2,R7-1), (R1-2, R2-2, R3-1, Pr-2, R7-2), (R1-2, R2-2, R3-1, Pr-2, R7-3),(R1-2, R2-2, R3-1, Pr-3, R7-1), (R1-2, R2-2, R3-1, Pr-3, R7-2), (R1-2,R2-2, R3-1, Pr-3, R7-3), (R1-2, R2-2, R3-1, Pr-4, R7-1), (R1-2, R2-2,R3-1, Pr-4, R7-2), (R1-2, R2-2, R3-1, Pr-4, R7-3), (R1-2, R2-2, R3-2,Pr-1, R7-1), (R1-2, R2-2, R3-2, Pr-1, R7-2), (R1-2, R2-2, R3-2, Pr-1,R7-3), (R1-2, R2-2, R3-2, Pr-2, R7-1), (R1-2, R2-2, R3-2, Pr-2, R7-2),(R1-2, R2-2, R3-2, Pr-2, R7-3), (R1-2, R2-2, R3-2, Pr-3, R7-1), (R1-2,R2-2, R3-2, Pr-3, R7-2), (R1-2, R2-2, R3-2, Pr-3, R7-3), (R1-2, R2-2,R3-2, Pr-4, R7-1), (R1-2, R2-2, R3-2, Pr-4, R7-2), (R1-2, R2-2, R3-2,Pr-4, R7-3), (R1-2, R2-2, R3-3, Pr-1, R7-1), (R1-2, R2-2, R3-3, Pr-1,R7-2), (R1-2, R2-2, R3-3, Pr-1, R7-3), (R1-2, R2-2, R3-3, Pr-2, R7-1),(R1-2, R2-2, R3-3, Pr-2, R7-2), (R1-2, R2-2, R3-3, Pr-2, R7-3), (R1-2,R2-2, R3-3, Pr-3, R7-1), (R1-2, R2-2, R3-3, Pr-3, R7-2), (R1-2, R2-2,R3-3, Pr-3, R7-3), (R1-2, R2-2, R3-3, Pr-4, R7-1), (R1-2, R2-2, R3-3,Pr-4, R7-2), (R1-2, R2-2, R3-3, Pr-4, R7-3), (R1-2, R2-2, R3-4, Pr-1,R7-1), (R1-2, R2-2, R3-4, Pr-1, R7-2), (R1-2, R2-2, R3-4, Pr-1, R7-3),(R1-2, R2-2, R3-4, Pr-2, R7-1), (R1-2, R2-2, R3-4, Pr-2, R7-2), (R1-2,R2-2, R3-4, Pr-2, R7-3), (R1-2, R2-2, R3-4, Pr-3, R7-1), (R1-2, R2-2,R3-4, Pr-3, R7-2), (R1-2, R2-2, R3-4, Pr-3, R7-3), (R1-2, R2-2, R3-4,Pr-4, R7-1), (R1-2, R2-2, R3-4, Pr-4, R7-2), (R1-2, R2-2, R3-4, Pr-4,R7-3), (R1-2, R2-2, R3-5, Pr-1, R7-1), (R1-2, R2-2, R3-5, Pr-1, R7-2),(R1-2, R2-2, R3-5, Pr-1, R7-3), (R1-2, R2-2, R3-5, Pr-2, R7-1), (R1-2,R2-2, R3-5, Pr-2, R7-2), (R1-2, R2-2, R3-5, Pr-2, R7-3), (R1-2, R2-2,R3-5, Pr-3, R7-1), (R1-2, R2-2, R3-5, Pr-3, R7-2), (R1-2, R2-2, R3-5,Pr-3, R7-3), (R1-2, R2-2, R3-5, Pr-4, R7-1), (R1-2, R2-2, R3-5, Pr-4,R7-2), (R1-2, R2-2, R3-5, Pr-4, R7-3),

(R1-3, R2-1, R3-1, Pr-1, R7-1), (R1-3, R2-1, R3-1, Pr-1, R7-2), (R1-3,R2-1, R3-1, Pr-1, R7-3), (R1-3, R2-1, R3-1, Pr-2, R7-1), (R1-3, R2-1,R3-1, Pr-2, R7-2), (R1-3, R2-1, R3-1, Pr-2, R7-3), (R1-3, R2-1, R3-1,Pr-3, R7-1), (R1-3, R2-1, R3-1, Pr-3, R7- 2), (R1-3, R2-1, R3-1, Pr-3,R7-3), (R1-3, R2-1, R3-1, Pr-4, R7-1), (R1-3, R2-1, R3-1, Pr-4, R7-2),(R1-3, R2-1, R3-1, Pr-4, R7-3), (R1-3, R2-1, R3-2, Pr-1, R7-1), (R1-3,R2-1, R3-2, Pr-1, R7-2), (R1-3, R2-1, R3-2, Pr-1, R7-3), (R1-3, R2-1,R3-2, Pr-2, R7-1), (R1-3, R2-1, R3-2, Pr-2, R7-2), (R1-3, R2-1, R3-2,Pr-2, R7-3), (R1-3, R2-1, R3-2, Pr-3, R7-1), (R1-3, R2-1, R3-2, Pr-3,R7-2), (R1-3, R2-1, R3-2, Pr-3, R7-3), (R1-3, R2-1, R3-2, Pr-4, R7-1),(R1-3, R2-1, R3-2, Pr-4, R7-2), (R1-3, R2-1, R3-2, Pr-4, R7-3), (R1-3,R2-1, R3-3, Pr-1, R7-1), (R1-3, R2-1, R3-3, Pr-1, R7-2), (R1-3, R2-1,R3-3, Pr-1, R7-3), (R1-3, R2-1, R3-3, Pr-2, R7-1), (R1-3, R2-1, R3-3,Pr-2, R7-2), (R1-3, R2-1, R3-3, Pr-2, R7-3), (R1-3, R2-1, R3-3, Pr-3,R7-1), (R1-3, R2-1, R3-3, Pr-3, R7-2), (R1-3, R2-1, R3-3, Pr-3, R7-3),(R1-3, R2-1, R3-3, Pr-4, R7-1), (R1-3, R2-1, R3-3, Pr-4, R7-2), (R1-3,R2-1, R3-3, Pr-4, R7-3), (R1-3, R2-1, R3-4, Pr-1, R7-1), (R1-3, R2-1,R3-4, Pr-1, R7-2), (R1-3, R2-1, R3-4, Pr-1, R7-3), (R1-3, R2-1, R3-4,Pr-2, R7-1), (R1-3, R2-1, R3-4, Pr-2, R7-2), (R1-3, R2-1, R3-4, Pr-2,R7-3), (R1-3, R2-1, R3-4, Pr-3, R7-1), (R1-3, R2-1, R3-4, Pr-3, R7-2),(R1-3, R2-1, R3-4, Pr-3, R7-3), (R1-3, R2-1, R3-4, Pr-4, R7-1), (R1-3,R2-1, R3-4, Pr-4, R7-2), (R1-3, R2-1, R3-4, Pr-4, R7-3), (R1-3, R2-1,R3-5, Pr-1, R7-1), (R1-3, R2-1, R3-5, Pr-1, R7-2), (R1-3, R2-1, R3-5,Pr-1, R7-3), (R1-3, R2-1, R3-5, Pr-2, R7-1), (R1-3, R2-1, R3-5, Pr-2,R7-2), (R1-3, R2-1, R3-5, Pr-2, R7-3), (R1-3, R2-1, R3-5, Pr-3, R7-1),(R1-3, R2-1, R3-5, Pr-3, R7-2), (R1-3, R2-1, R3-5, Pr-3, R7-3), (R1-3,R2-1, R3-5, Pr-4, R7-1), (R1-3, R2-1, R3-5, Pr-4, R7-2), (R1-3, R2-1,R3-5, Pr-4, R7-3), (R1-3, R2-2, R3-1, Pr-1, R7-1), (R1-3, R2-2, R3-1,Pr-1, R7-2), (R1-3, R2-2, R3-1, Pr-1, R7-3), (R1-3, R2-2, R3-1, Pr-2,R7-1), (R1-3, R2-2, R3-1, Pr-2, R7-2), (R1-3, R2-2, R3-1, Pr-2, R7-3),(R1-3, R2-2, R3-1, Pr-3, R7-1), (R1-3, R2-2, R3-1, Pr-3, R7-2), (R1-3,R2-2, R3-1, Pr-3, R7-3), (R1-3, R2-2, R3-1, Pr-4, R7-1), (R1-3, R2-2,R3-1, Pr-4, R7-2), (R1-3, R2-2, R3-1, Pr-4, R7-3), (R1-3, R2-2, R3-2,Pr-1, R7-1), (R1-3, R2-2, R3-2, Pr-1, R7-2), (R1-3, R2-2, R3-2, Pr-1,R7-3), (R1-3, R2-2, R3-2, Pr-2, R7-1), (R-3, R2-2, R3-2, Pr-2, R7-2),(R1-3, R2-2, R3-2, Pr-2, R7-3), (R1-3, R2-2, R3-2, Pr-3, R7-1), (R1-3,R2-2, R3-2, Pr-3, R7-2), (R1-3, R2-2, R3-2, Pr-3, R7-3), (R1-3, R2-2,R3-2, Pr-4, R7-1), (R1-3, R2-2, R3-2, Pr-4, R7-2), (R1-3, R2-2, R3-2,Pr-4, R7-3), (R1-3, R2-2, R3-3, Pr-1, R7-1), (R1-3, R2-2, R3-3, Pr-1,R7-2), (R1-3, R2-2, R3-3, Pr-1, R7-3), (R1-3, R2-2, R3-3, Pr-2, R7-1),(R1-3, R2-2, R3-3, Pr-2, R7-2), (R1-3, R2-2, R3-3, Pr-2, R7-3), (R1-3,R2-2, R3-3, Pr-3, R7-1), (R1-3, R2-2, R3-3, Pr-3, R7-2), (R-3, R2-2,R3-3, Pr-3, R7-3), (R1-3, R2-2, R3-3, Pr-4, R7-1), (R1-3, R2-2, R3-3,Pr-4, R7-2), (R1-3, R2-2, R3-3, Pr-4, R7-3), (R1-3, R2-2, R3-4, Pr-1,R7-1), (R-3, R2-2, R3-4, Pr-1, R7-2), (R1-3, R2-2, R3-4, Pr-1, R7-3),(R1-3, R2-2, R3-4, Pr-2, R7-1), (R-3, R2-2, R3-4, Pr-2, R7-2), (R1-3,R2-2, R3-4, Pr-2, R7-3), (R1-3, R2-2, R3-4, Pr-3, R7-1), (R1-3, R2-2,R3-4, Pr-3, R7-2), (R1-3, R2-2, R3-4, Pr-3, R7-3), (R1-3, R2-2, R3-4,Pr-4, R7-1), (R1-3, R2-2, R3-4, Pr-4, R7-2), (R1-3, R2-2, R3-4, Pr-4,R7-3), (R1-3, R2-2, R3-5, Pr-1, R7-1), (R1-3, R2-2, R3-5, Pr-1, R7-2),(R1-3, R2-2, R3-5, Pr-1, R7-3), (R1-3, R2-2, R3-5, Pr-2, R7-1), (R1-3,R2-2, R3-5, Pr-2, R7-2), (R1-3, R2-2, R3-5, Pr-2, R7-3), (R1-3, R2-2,R3-5, Pr-3, R7-1), (R1-3, R2-2, R3-5, Pr-3, R7-2), (R-3, R2-2, R3-5,Pr-3, R7-3), (R1-3, R2-2, R3-5, Pr-4, R7-1), (R1-3, R2-2, R3-5, Pr-4,R7-2), (R1-3, R2-2, R3-5, Pr-4, R7-3),

(R1-4, R2-1, R3-1, Pr-1, R7-1), (R1-4, R2-1, R3-1, Pr-1, R7-2), (R1-4,R2-1, R3-1, Pr-1, R7-3), (R1-4, R2-1, R3-1, Pr-2, R7-1), (R1-4, R2-1,R3-1, Pr-2, R7-2), (R1-4, R2-1, R3-1, Pr-2, R7-3), (R1-4, R2-1, R3-1,Pr-3, R7-1), (R1-4, R2-1, R3-1, Pr-3, R7- 2), (R1-4, R2-1, R3-1, Pr-3,R7-3), (R1-4, R2-1, R3-1, Pr-4, R7-1), (R1-4, R2-1, R3-1, Pr-4, R7-2),(R1-4, R2-1, R3-1, Pr-4, R7-3), (R1-4, R2-1, R3-2, Pr-1, R7-1), (R1-4,R2-1, R3-2, Pr-1, R7-2), (R1-4, R2-1, R3-2, Pr-1, R7-3), (R1-4, R2-1,R3-2, Pr-2, R7-1), (R1-4, R2-1, R3-2, Pr-2, R7-2), (R1-4, R2-1, R3-2,Pr-2, R7-3), (R1-4, R2-1, R3-2, Pr-3, R7-1), (R1-4, R2-1, R3-2, Pr-3,R7-2), (R1-4, R2-1, R3-2, Pr-3, R7-3), (R1-4, R2-1, R3-2, Pr-4, R7-1),(R1-4, R2-1, R3-2, Pr-4, R7-2), (R1-4, R2-1, R3-2, Pr-4, R7-3), (R1-4,R2-1, R3-3, Pr-1, R7-1), (R1-4, R2-1, R3-3, Pr-1, R7-2), (R1-4, R2-1,R3-3, Pr-1, R7-3), (R1-4, R2-1, R3-3, Pr-2, R7-1), (R1-4, R2-1, R3-3,Pr-2, R7-2), (R1-4, R2-1, R3-3, Pr-2, R7-3), (R1-4, R2-1, R3-3, Pr-3,R7-1), (R1-4, R2-1, R3-3, Pr-3, R7-2), (R1-4, R2-1, R3-3, Pr-3, R7-3),(R1-4, R2-1, R3-3, Pr-4, R7-1), (R1-4, R2-1, R3-3, Pr-4, R7-2), (R1-4,R2-1, R3-3, Pr-4, R7-3), (R1-4, R2-1, R3-4, Pr-1, R7-1), (R1-4, R2-1,R3-4, Pr-1, R7-2), (R1-4, R2-1, R3-4, Pr-1, R7-3), (R1-4, R2-1, R3-4,Pr-2, R7-1), (R1-4, R2-1, R3-4, Pr-2, R7-2), (R1-4, R2-1, R3-4, Pr-2,R7-3), (R1-4, R2-1, R3-4, Pr-3, R7-1), (R1-4, R2-1, R3-4, Pr-3, R7-2),(R1-4, R2-1, R3-4, Pr-3, R7-3), (R1-4, R2-1, R3-4, Pr-4, R7-1), (R1-4,R2-1, R3-4, Pr-4, R7-2), (R1-4, R2-1, R3-4, Pr-4, R7-3), (R1-4, R2-1,R3-5, Pr-1, R7-1), (R1-4, R2-1, R3-5, Pr-1, R7-2), (R1-4, R2-1, R3-5,Pr-1, R7-3), (R1-4, R2-1, R3-5, Pr-2, R7-1), (R1-4, R2-1, R3-5, Pr-2,R7-2), (R1-4, R2-1, R3-5, Pr-2, R7-3), (R1-4, R2-1, R3-5, Pr-3, R7-1),(R1-4, R2-1, R3-5, Pr-3, R7-2), (R1-4, R2-1, R3-5, Pr-3, R7-3), (R1-4,R2-1, R3-5, Pr-4, R7-1), (R1-4, R2-1, R3-5, Pr-4, R7-2), (R-4, R2-1,R3-5, Pr-4, R7-3), (R1-4, R2-2, R3-1, Pr-1, R7-1), (R1-4, R2-2, R3-1,Pr-1, R7-2), (R1-4, R2-2, R3-1, Pr-1, R7-3), (R1-4, R2-2, R3-1, Pr-2,R7-1), (R1-4, R2-2, R3-1, Pr-2, R7-2), (R1-4, R2-2, R3-1, Pr-2, R7-3),(R1-4, R2-2, R3-1, Pr-3, R7-1), (R1-4, R2-2, R3-1, Pr-3, R7-2), ((R1-4,R2-2, R3-1, Pr-3, R7-3), (R1-4, R2-2, R3-1, Pr-4, R7-1), (R1-4, R2-2,R3-1, Pr-4, R7-2), (R1-4, R2-2, R3-1, Pr-4, R7-3), (R1-4, R2-2, R3-2,Pr-1, R7-1), (R1-4, R2-2, R3-2, Pr-1, R7-2), (R1-4, R2-2, R3-2, Pr-1,R7-3), (R1-4, R2-2, R3-2, Pr-2, R7-1), (R1-4, R2-2, R3-2, Pr-2, R7-2),(R1-4, R2-2, R3-2, Pr-2, R7-3), (R1-4, R2-2, R3-2, Pr-3, R7-1), (R1-4,R2-2, R3-2, Pr-3, R7-2), (R1-4, R2-2, R3-2, Pr-3, R7-3), (R1-4, R2-2,R3-2, Pr-4, R7-1), (R1-4, R2-2, R3-2, Pr-4, R7-2), (R1-4, R2-2, R3-2,Pr-4, R7-3), (R1-4, R2-2, R3-3, Pr-1, R7-1), (R1-4, R2-2, R3-3, Pr-1,R7-2), (R1-4, R2-2, R3-3, Pr-1, R7-3), (R1-4, R2-2, R3-3, Pr-2, R7-1),(R1-4, R2-2, R3-3, Pr-2, R7-2), (R1-4, R2-2, R3-3, Pr-2, R7-3), (R1-4,R2-2, R3-3, Pr-3, R7-1), (R1-4, R2-2, R3-3, Pr-3, R7-2), (R-4, R2-2,R3-3, Pr-3, R7-3), (R1-4, R2-2, R3-3, Pr-4, R7-1), (R1-4, R2-2, R3-3,Pr-4, R7-2), (R1-4, R2-2, R3-3, Pr-4, R7-3), (R1-4, R2-2, R3-4, Pr-1,R7-1), (R-4, R2-2, R3-4, Pr-1, R7-2), (R1-4, R2-2, R3-4, Pr-1, R7-3),(R1-4, R2-2, R3-4, Pr-2, R7-1), (R-4, R2-2, R3-4, Pr-2, R7-2), (R1-4,R2-2, R3-4, Pr-2, R7-3), (R1-4, R2-2, R3-4, Pr-3, R7-1), (R1-4, R2-2,R3-4, Pr-3, R7-2), (R1-4, R2-2, R3-4, Pr-3, R7-3), (R1-4, R2-2, R3-4,Pr-4, R7-1), (R1-4, R2-2, R3-4, Pr-4, R7-2), (R1-4, R2-2, R3-4, Pr-4,R7-3), (R1-4, R2-2, R3-5, Pr-1, R7-1), (R1-4, R2-2, R3-5, Pr-1, R7-2),(R1-4, R2-2, R3-5, Pr-1, R7-3), (R1-4, R2-2, R3-5, Pr-2, R7-1), (R1-4,R2-2, R3-5, Pr-2, R7-2), (R1-4, R2-2, R3-5, Pr-2, R7-3), (R1-4, R2-2,R3-5, Pr-3, R7-1), (R1-4, R2-2, R3-5, Pr-3, R7-2), (R-4, R2-2, R3-5,Pr-3, R7-3), (R1-4, R2-2, R3-5, Pr-4, R7-1), (R1-4, R2-2, R3-5, Pr-4,R7-2), (R1-4, R2-2, R3-5, Pr-4, R7-3),

(R1-5, R2-1, R3-1, Pr-1, R7-1), (R1-5, R2-1, R3-1, Pr-1, R7-2), (R1-5,R2-1, R3-1, Pr-1, R7-3), (R1-5, R2-1, R3-1, Pr-2, R7-1), (R1-5, R2-1,R3-1, Pr-2, R7-2), (R1-5, R2-1, R3-1, Pr-2, R7-3), (R1-5, R2-1, R3-1,Pr-3, R7-1), (R1-5, R2-1, R3-1, Pr-3, R7- 2), (R1-5, R2-1, R3-1, Pr-3,R7-3), (R1-5, R2-1, R3-1, Pr-4, R7-1), (R1-5, R2-1, R3-1, Pr-4, R7-2),(R1-5, R2-1, R3-1, Pr-4, R7-3), (R1-5, R2-1, R3-2, Pr-1, R7-1), (R1-5,R2-1, R3-2, Pr-1, R7-2), (R1-5, R2-1, R3-2, Pr-1, R7-3), (R1-5, R2-1,R3-2, Pr-2, R7-1), (R1-5, R2-1, R3-2, Pr-2, R7-2), (R1-5, R2-1, R3-2,Pr-2, R7-3), (R1-5, R2-1, R3-2, Pr-3, R7-1), (R1-5, R2-1, R3-2, Pr-3,R7-2), (R1-5, R2-1, R3-2, Pr-3, R7-3), (R1-5, R2-1, R3-2, Pr-4, R7-1),(R1-5, R2-1, R3-2, Pr-4, R7-2), (R1-5, R2-1, R3-2, Pr-4, R7-3), (R1-5,R2-1, R3-3, Pr-1, R7-1), (R1-5, R2-1, R3-3, Pr-1, R7-2), (R1-5, R2-1,R3-3, Pr-1, R7-3), (R1-5, R2-1, R3-3, Pr-2, R7-1), (R1-5, R2-1, R3-3,Pr-2, R7-2), (R1-5, R2-1, R3-3, Pr-2, R7-3), (R1-5, R2-1, R3-3, Pr-3,R7-1), (R1-5, R2-1, R3-3, Pr-3, R7-2), (R1-5, R2-1, R3-3, Pr-3, R7-3),(R1-5, R2-1, R3-3, Pr-4, R7-1), (R1-5, R2-1, R3-3, Pr-4, R7-2), (R1-5,R2-1, R3-3, Pr-4, R7-3), (R1-5, R2-1, R3-4, Pr-1, R7-1), (R1-5, R2-1,R3-4, Pr-1, R7-2), (R1-5, R2-1, R3-4, Pr-1, R7-3), (R1-5, R2-1, R3-4,Pr-2, R7-1), (R1-5, R2-1, R3-4, Pr-2, R7-2), (R1-5, R2-1, R3-4, Pr-2,R7-3), (R1-5, R2-1, R3-4, Pr-3, R7-1), (R1-5, R2-1, R3-4, Pr-3, R7-2),(R1-5, R2-1, R3-4, Pr-3, R7-3), (R1-5, R2-1, R3-4, Pr-4, R7-1), (R1-5,R2-1, R3-4, Pr-4, R7-2), (R1-5, R2-1, R3-4, Pr-4, R7-3), (R1-5, R2-1,R3-5, Pr-1, R7-1), (R1-5, R2-1, R3-5, Pr-1, R7-2), (R1-5, R2-1, R3-5,Pr-1, R7-3), (R1-5, R2-1, R3-5, Pr-2, R7-1), (R1-5, R2-1, R3-5, Pr-2,R7-2), (R1-5, R2-1, R3-5, Pr-2, R7-3), (R1-5, R2-1, R3-5, Pr-3, R7-1),(R1-5, R2-1, R3-5, Pr-3, R7-2), (R1-5, R2-1, R3-5, Pr-3, R7-3), (R1-5,R2-1, R3-5, Pr-4, R7-1), (R1-5, R2-1, R3-5, Pr-4, R7-2), (R1-5, R2-1,R3-5, Pr-4, R7-3), (R1-5, R2-2, R3-1, Pr-1, R7-1), (R1-5, R2-2, R3-1,Pr-1, R7-2), (R1-5, R2-2, R3-1, Pr-1, R7-3), (R1-5, R2-2, R3-1, Pr-2,R7-1), (R1-5, R2-2, R3-1, Pr-2, R7-2), (R1-5, R2-2, R3-1, Pr-2, R7-3),(R1-5, R2-2, R3-1, Pr-3, R7-1), (R1-5, R2-2, R3-1, Pr-3, R7-2), (R1-5,R2-2, R3-1, Pr-3, R7-3), (R1-5, R2-2, R3-1, Pr-4, R7-1), (R1-5, R2-2,R3-1, Pr-4, R7-2), (R1-5, R2-2, R3-1, Pr-4, R7-3), (R1-5, R2-2, R3-2,Pr-1, R7-1), (R1-5, R2-2, R3-2, Pr-1, R7-2), (R1-5, R2-2, R3-2, Pr-1,R7-3), (R1-5, R2-2, R3-2, Pr-2, R7-1), (R1-5, R2-2, R3-2, Pr-2, R7-2),(R1-5, R2-2, R3-2, Pr-2, R7-3), (R1-5, R2-2, R3-2, Pr-3, R7-1), (R1-5,R2-2, R3-2, Pr-3, R7-2), (R1-5, R2-2, R3-2, Pr-3, R7-3), (R1-5, R2-2,R3-2, Pr-4, R7-1), (R1-5, R2-2, R3-2, Pr-4, R7-2), (R1-5, R2-2, R3-2,Pr-4, R7-3), (R1-5, R2-2, R3-3, Pr-1, R7-1), (R1-5, R2-2, R3-3, Pr-1,R7-2), R1-5, R2-2, R3-3, Pr-1, R7-3), (R1-5, R2-2, R3-3, Pr-2, R7-1),(R1-5, R2-2, R3-3, Pr-2, R7-2), (R1-5, R2-2, R3-3, Pr-2, R7-3), (R1-5,R2-2, R3-3, Pr-3, R7-1), (R1-5, R2-2, R3-3, Pr-3, R7-2), (R1-5, R2-2,R3-3, Pr-3, R7-3), (R1-5, R2-2, R3-3, Pr-4, R7-1), (R1-5, R2-2, R3-3,Pr-4, R7-2), (R1-5, R2-2, R3-3, Pr-4, R7-3), (R1-5, R2-2, R3-4, Pr-1,R7-1), (R-5, R2-2, R3-4, Pr-1, R7-2), (R1-5, R2-2, R3-4, Pr-1, R7-3),(R1-5, R2-2, R3-4, Pr-2, R7-1), (R-5, R2-2, R3-4, Pr-2, R7-2), (R1-5,R2-2, R3-4, Pr-2, R7-3), (R1-5, R2-2, R3-4, Pr-3, R7-1), (R1-5, R2-2,R3-4, Pr-3, R7-2), (R1-5, R2-2, R3-4, Pr-3, R7-3), (R1-5, R2-2, R3-4,Pr-4, R7-1), (R1-5, R2-2, R3-4, Pr-4, R7-2), (R1-5, R2-2, R3-4, Pr-4,R7-3), (R1-5, R2-2, R3-5, Pr-1, R7-1), (R1-5, R2-2, R3-5, Pr-1, R7-2),(R1-5, R2-2, R3-5, Pr-1, R7-3), (R1-5, R2-2, R3-5, Pr-2, R7-1), (R1-5,R2-2, R3-5, Pr-2, R7-2), (R1-5, R2-2, R3-5, Pr-2, R7-3), (R1-5, R2-2,R3-5, Pr-3, R7-1), (R1-5, R2-2, R3-5, Pr-3, R7-2), (R-5, R2-2, R3-5,Pr-3, R7-3), (R1-5, R2-2, R3-5, Pr-4, R7-1), (R1-5, R2-2, R3-5, Pr-4,R7-2), (R1-5, R2-2, R3-5, Pr-4, R7-3),

(R1-6, R2-1, R3-1, Pr-1, R7-1), (R1-6, R2-1, R3-1, Pr-1, R7-2), (R1-6,R2-1, R3-1, Pr-1, R7-3), (R1-6, R2-1, R3-1, Pr-2, R7-1), (R1-6, R2-1,R3-1, Pr-2, R7-2), (R1-6, R2-1, R3-1, Pr-2, R7-3), (R1-6, R2-1, R3-1,Pr-3, R7-1), (R1-6, R2-1, R3-1, Pr-3, R7- 2), (R1-6, R2-1, R3-1, Pr-3,R7-3), (R1-6, R2-1, R3-1, Pr-4, R7-1), (R1-6, R2-1, R3-1, Pr-4, R7-2),(R1-6, R2-1, R3-1, Pr-4, R7-3), (R1-6, R2-1, R3-2, Pr-1, R7-1), (R1-6,R2-1, R3-2, Pr-1, R7-2), (R1-6, R2-1, R3-2, Pr-1, R7-3), (R1-6, R2-1,R3-2, Pr-2, R7-1), (R1-6, R2-1, R3-2, Pr-2, R7-2), (R1-6, R2-1, R3-2,Pr-2, R7-3), (R1-6, R2-1, R3-2, Pr-3, R7-1), (R1-6, R2-1, R3-2, Pr-3,R7-2), (R1-6, R2-1, R3-2, Pr-3, R7-3), (R1-6, R2-1, R3-2, Pr-4, R7-1),(R1-6, R2-1, R3-2, Pr-4, R7-2), (R1-6, R2-1, R3-2, Pr-4, R7-3), (R1-6,R2-1, R3-3, Pr-1, R7-1), (R1-6, R2-1, R3-3, Pr-1, R7-2), (R1-6, R2-1,R3-3, Pr-1, R7-3), (R1-6, R2-1, R3-3, Pr-2, R7-1), (R1-6, R2-1, R3-3,Pr-2, R7-2), (R1-6, R2-1, R3-3, Pr-2, R7-3), (R1-6, R2-1, R3-3, Pr-3,R7-1), (R1-6, R2-1, R3-3, Pr-3, R7-2), (R1-6, R2-1, R3-3, Pr-3, R7-3),(R1-6, R2-1, R3-3, Pr-4, R7-1), (R1-6, R2-1, R3-3, Pr-4, R7-2), (R1-6,R2-1, R3-3, Pr-4, R7-3), (R1-6, R2-1, R3-4, Pr-1, R7-1), (R1-6, R2-1,R3-4, Pr-1, R7-2), (R1-6, R2-1, R3-4, Pr-1, R7-3), (R1-6, R2-1, R3-4,Pr-2, R7-1), (R1-6, R2-1, R3-4, Pr-2, R7-2), (R1-6, R2-1, R3-4, Pr-2,R7-3), (R1-6, R2-1, R3-4, Pr-3, R7-1), (R1-6, R2-1, R3-4, Pr-3, R7-2),(R1-6, R2-1, R3-4, Pr-3, R7-3), (R1-6, R2-1, R3-4, Pr-4, R7-1), (R1-6,R2-1, R3-4, Pr-4, R7-2), (R1-6, R2-1, R3-4, Pr-4, R7-3), (R1-6, R2-1,R3-5, Pr-1, R7-1), (R1-6, R2-1, R3-5, Pr-1, R7-2), (R1-6, R2-1, R3-5,Pr-1, R7-3), (R1-6, R2-1, R3-5, Pr-2, R7-1), (R1-6, R2-1, R3-5, Pr-2,R7-2), (R1-6, R2-1, R3-5, Pr-2, R7-3), (R1-6, R2-1, R3-5, Pr-3, R7-1),(R1-6, R2-1, R3-5, Pr-3, R7-2), (R1-6, R2-1, R3-5, Pr-3, R7-3), (R1-6,R2-1, R3-5, Pr-4, R7-1), (R1-6, R2-1, R3-5, Pr-4, R7-2), (R1-6, R2-1,R3-5, Pr-4, R7-3), (R1-6, R2-2, R3-1, Pr-1, R7-1), (R1-6, R2-2, R3-1,Pr-1, R7-2), (R1-6, R2-2, R3-1, Pr-1, R7-3), (R1-6, R2-2, R3-1, Pr-2,R7-1), (R1-6, R2-2, R3-1, Pr-2, R7-2), (R1-6, R2-2, R3-1, Pr-2, R7-3),(R1-6, R2-2, R3-1, Pr-3, R7-1), (R1-6, R2-2, R3-1, Pr-3, R7-2), (R1-6,R2-2, R3-1, Pr-3, R7-3), (R1-6, R2-2, R3-1, Pr-4, R7-1), (R1-6, R2-2,R3-1, Pr-4, R7-2), (R1-6, R2-2, R3-1, Pr-4, R7-3), (R1-6, R2-2, R3-2,Pr-1, R7-1), (R1-6, R2-2, R3-2, Pr-1, R7-2), (R1-6, R2-2, R3-2, Pr-1,R7-3), (R1-6, R2-2, R3-2, Pr-2, R7-1), (R1-6, R2-2, R3-2, Pr-2, R7-2),(R1-6, R2-2, R3-2, Pr-2, R7-3), (R1-6, R2-2, R3-2, Pr-3, R7-1), (R1-6,R2-2, R3-2, Pr-3, R7-2), (R1-6, R2-2, R3-2, Pr-3, R7-3), (R1-6, R2-2,R3-2, Pr-4, R7-1), (R1-6, R2-2, R3-2, Pr-4, R7-2), (R1-6, R2-2, R3-2,Pr-4, R7-3), (R1-6, R2-2, R3-3, Pr-1, R7-1), (R1-6, R2-2, R3-3, Pr-1,R7-2), (R1-6, R2-2, R3-3, Pr-1, R7-3), (R1-6, R2-2, R3-3, Pr-2, R7-1),(R1-6, R2-2, R3-3, Pr-2, R7-2), (R1-6, R2-2, R3-3, Pr-2, R7-3), (R1-6,R2-2, R3-3, Pr-3, R7-1), (R1-6, R2-2, R3-3, Pr-3, R7-2), (R1-6, R2-2,R3-3, Pr-3, R7-3), (R1-6, R2-2, R3-3, Pr-4, R7-1), (R1-6, R2-2, R3-3,Pr-4, R7-2), (R1-6, R2-2, R3-3, Pr-4, R7-3), (R1-6, R2-2, R3-4, Pr-1,R7-1), (R1-6, R2-2, R3-4, Pr-1, R7-2), (R1-6, R2-2, R3-4, Pr-1, R7-3),(R1-6, R2-2, R3-4, Pr-2, R7-1), (R-6, R2-2, R3-4, Pr-2, R7-2), (R1-6,R2-2, R3-4, Pr-2, R7-3), (R1-6, R2-2, R3-4, Pr-3, R7-1), (R1-6, R2-2,R3-4, Pr-3, R7-2), (R1-6, R2-2, R3-4, Pr-3, R7-3), (R1-6, R2-2, R3-4,Pr-4, R7-1), (R1-6, R2-2, R3-4, Pr-4, R7-2), (R1-6, R2-2, R3-4, Pr-4,R7-3), (R1-6, R2-2, R3-5, Pr-1, R7-1), (R1-6, R2-2, R3-5, Pr-1, R7-2),(R1-6, R2-2, R3-5, Pr-1, R7-3), (R1-6, R2-2, R3-5, Pr-2, R7-1), (R1-6,R2-2, R3-5, Pr-2, R7-2), (R1-6, R2-2, R3-5, Pr-2, R7-3), (R1-6, R2-2,R3-5, Pr-3, R7-1), (R1-6, R2-2, R3-5, Pr-3, R7-2), (R-6, R2-2, R3-5,Pr-3, R7-3), (R1-6, R2-2, R3-5, Pr-4, R7-1), (R1-6, R2-2, R3-5, Pr-4,R7-2), (R1-6, R2-2, R3-5, Pr-4, R7-3),

(R1-7, R2-1, R3-1, Pr-1, R7-1), (R1-7, R2-1, R3-1, Pr-1, R7-2), (R1-7,R2-1, R3-1, Pr-1, R7-3), (R1-7, R2-1, R3-1, Pr-2, R7-1), (R1-7, R2-1,R3-1, Pr-2, R7-2), (R1-7, R2-1, R3-1, Pr-2, R7-3), (R1-7, R2-1, R3-1,Pr-3, R7-1), (R1-7, R2-1, R3-1, Pr-3, R7- 2), (R1-7, R2-1, R3-1, Pr-3,R7-3), (R1-7, R2-1, R3-1, Pr-4, R7-1), (R1-7, R2-1, R3-1, Pr-4, R7-2),(R1-7, R2-1, R3-1, Pr-4, R7-3), (R1-7, R2-1, R3-2, Pr-1, R7-1), (R1-7,R2-1, R3-2, Pr-1, R7-2), (R1-7, R2-1, R3-2, Pr-1, R7-3), (R1-7, R2-1,R3-2, Pr-2, R7-1), (R1-7, R2-1, R3-2, Pr-2, R7-2), (R1-7, R2-1, R3-2,Pr-2, R7-3), (R1-7, R2-1, R3-2, Pr-3, R7-1), (R1-7, R2-1, R3-2, Pr-3,R7-2), (R1-7, R2-1, R3-2, Pr-3, R7-3), (R1-7, R2-1, R3-2, Pr-4, R7-1),(R1-7, R2-1, R3-2, Pr-4, R7-2), (R1-7, R2-1, R3-2, Pr-4, R7-3), (R1-7,R2-1, R3-3, Pr-1, R7-1), (R1-7, R2-1, R3-3, Pr-1, R7-2), (R1-7, R2-1,R3-3, Pr-1, R7-3), (R1-7, R2-1, R3-3, Pr-2, R7-1), (R1-7, R2-1, R3-3,Pr-2, R7-2), (R1-7, R2-1, R3-3, Pr-2, R7-3), (R1-7, R2-1, R3-3, Pr-3,R7-1), (R1-7, R2-1, R3-3, Pr-3, R7-2), (R1-7, R2-1, R3-3, Pr-3, R7-3),(R1-7, R2-1, R3-3, Pr-4, R7-1), (R1-7, R2-1, R3-3, Pr-4, R7-2), (R1-7,R2-1, R3-3, Pr-4, R7-3), (R1-7, R2-1, R3-4, Pr-1, R7-1), (R1-7, R2-1,R3-4, Pr-1, R7-2), (R1-7, R2-1, R3-4, Pr-1, R7-3), (R1-7, R2-1, R3-4,Pr-2, R7-1), (R1-7, R2-1, R3-4, Pr-2, R7-2), (R1-7, R2-1, R3-4, Pr-2,R7-3), (R1-7, R2-1, R3-4, Pr-3, R7-1), (R1-7, R2-1, R3-4, Pr-3, R7-2),(R1-7, R2-1, R3-4, Pr-3, R7-3), (R1-7, R2-1, R3-4, Pr-4, R7-1), (R1-7,R2-1, R3-4, Pr-4, R7-2), (R1-7, R2-1, R3-4, Pr-4, R7-3), (R1-7, R2-1,R3-5, Pr-1, R7-1), (R-7, R2-1, R3-5, Pr-1, R7-2), (R1-7, R2-1, R3-5,Pr-1, R7-3), (R1-7, R2-1, R3-5, Pr-2, R7-1), (R1-7, R2-1, R3-5, Pr-2,R7-2), (R1-7, R2-1, R3-5, Pr-2, R7-3), (R1-7, R2-1, R3-5, Pr-3, R7-1),(R1-7, R2-1, R3-5, Pr-3, R7-2), (R1-7, R2-1, R3-5, Pr-3, R7-3), (R1-7,R2-1, R3-5, Pr-4, R7-1), (R1-7, R2-1, R3-5, Pr-4, R7-2), (R1-7, R2-1,R3-5, Pr-4, R7-3), (R1-7, R2-2, R3-1, Pr-1, R7-1), (R1-7, R2-2, R3-1,Pr-1, R7-2), (R1-7, R2-2, R3-1, Pr-1, R7-3), (R1-7, R2-2, R3-1, Pr-2,R7-1), (R1-7, R2-2, R3-1, Pr-2, R7-2), (R1-7, R2-2, R3-1, Pr-2, R7-3),(R1-7, R2-2, R3-1, Pr-3, R7-1), (R1-7, R2-2, R3-1, Pr-3, R7-2), (R1-7,R2-2, R3-1, Pr-3, R7-3), (R1-7, R2-2, R3-1, Pr-4, R7-1), (R1-7, R2-2,R3-1, Pr-4, R7-2), (R1-7, R2-2, R3-1, Pr-4, R7-3), (R1-7, R2-2, R3-2,Pr-1, R7-1), (R1-7, R2-2, R3-2, Pr-1, R7-2), (R1-7, R2-2, R3-2, Pr-1,R7-3), (R1-7, R2-2, R3-2, Pr-2, R7-1), (R1-7, R2-2, R3-2, Pr-2, R7-2),(R1-7, R2-2, R3-2, Pr-2, R7-3), (R1-7, R2-2, R3-2, Pr-3, R7-1), (R1-7,R2-2, R3-2, Pr-3, R7-2), (R1-7, R2-2, R3-2, Pr-3, R7-3), (R1-7, R2-2,R3-2, Pr-4, R7-1), (R1-7, R2-2, R3-2, Pr-4, R7-2), (R1-7, R2-2, R3-2,Pr-4, R7-3), (R1-7, R2-2, R3-3, Pr-1, R7-1), (R1-7, R2-2, R3-3, Pr-1,R7-2), (R1-7, R2-2, R3-3, Pr-1, R7-3), (R1-7, R2-2, R3-3, Pr-2, R7-1),(R1-7, R2-2, R3-3, Pr-2, R7-2), (R1-7, R2-2, R3-3, Pr-2, R7-3), (R1-7,R2-2, R3-3, Pr-3, R7-1), (R1-7, R2-2, R3-3, Pr-3, R7-2), (R1-7, R2-2,R3-3, Pr-3, R7-3), (R1-7, R2-2, R3-3, Pr-4, R7-1), (R1-7, R2-2, R3-3,Pr-4, R7-2), (R1-7, R2-2, R3-3, Pr-4, R7-3), (R1-7, R2-2, R3-4, Pr-1,R7-1), (R1-7, R2-2, R3-4, Pr-1, R7-2), (R1-7, R2-2, R3-4, Pr-1, R7-3),(R1-7, R2-2, R3-4, Pr-2, R7-1), (R1-7, R2-2, R3-4, Pr-2, R7-2), (R1-7,R2-2, R3-4, Pr-2, R7-3), (R1-7, R2-2, R3-4, Pr-3, R7-1), (R1-7, R2-2,R3-4, Pr-3, R7-2), (R1-7, R2-2, R3-4, Pr-3, R7-3), (R1-7, R2-2, R3-4,Pr-4, R7-1), (R1-7, R2-2, R3-4, Pr-4, R7-2), (R1-7, R2-2, R3-4, Pr-4,R7-3), (R1-7, R2-2, R3-5, Pr-1, R7-1), (R1-7, R2-2, R3-5, Pr-1, R7-2),(R1-7, R2-2, R3-5, Pr-1, R7-3), (R1-7, R2-2, R3-5, Pr-2, R7-1), (R1-7,R2-2, R3-5, Pr-2, R7-2), (R1-7, R2-2, R3-5, Pr-2, R7-3), (R1-7, R2-2,R3-5, Pr-3, R7-1), (R1-7, R2-2, R3-5, Pr-3, R7-2), (R1-7, R2-2, R3-5,Pr-3, R7-3), (R1-7, R2-2, R3-5, Pr-4, R7-1), (R1-7, R2-2, R3-5, Pr-4,R7-2), (R1-7, R2-2, R3-5, Pr-4, R7-3),

(R1-8, R2-1, R3-1, Pr-1, R7-1), (R1-8, R2-1, R3-1, Pr-1, R7-2), (R1-8,R2-1, R3-1, Pr-1, R7-3), (R1-8, R2-1, R3-1, Pr-2, R7-1), (R1-8, R2-1,R3-1, Pr-2, R7-2), (R1-8, R2-1, R3-1, Pr-2, R7-3), (R1-8, R2-1, R3-1,Pr-3, R7-1), (R1-8, R2-1, R3-1, Pr-3, R7- 2), (R1-8, R2-1, R3-1, Pr-3,R7-3), (R1-8, R2-1, R3-1, Pr-4, R7-1), (R1-8, R2-1, R3-1, Pr-4, R7-2),(R1-8, R2-1, R3-1, Pr-4, R7-3), (R1-8, R2-1, R3-2, Pr-1, R7-1), (R1-8,R2-1, R3-2, Pr-1, R7-2), (R1-8, R2-1, R3-2, Pr-1, R7-3), (R1-8, R2-1,R3-2, Pr-2, R7-1), (R1-8, R2-1, R3-2, Pr-2, R7-2), (R1-8, R2-1, R3-2,Pr-2, R7-3), (R1-8, R2-1, R3-2, Pr-3, R7-1), (R1-8, R2-1, R3-2, Pr-3,R7-2), (R1-8, R2-1, R3-2, Pr-3, R7-3), (R1-8, R2-1, R3-2, Pr-4, R7-1),(R1-8, R2-1, R3-2, Pr-4, R7-2), (R1-8, R2-1, R3-2, Pr-4, R7-3), (R1-8,R2-1, R3-3, Pr-1, R7-1), (R1-8, R2-1, R3-3, Pr-1, R7-2), (R1-8, R2-1,R3-3, Pr-1, R7-3), (R1-8, R2-1, R3-3, Pr-2, R7-1), (R1-8, R2-1, R3-3,Pr-2, R7-2), (R1-8, R2-1, R3-3, Pr-2, R7-3), (R1-8, R2-1, R3-3, Pr-3,R7-1), (R1-8, R2-1, R3-3, Pr-3, R7-2), (R1-8, R2-1, R3-3, Pr-3, R7-3),(R1-8, R2-1, R3-3, Pr-4, R7-1), (R1-8, R2-1, R3-3, Pr-4, R7-2), (R1-8,R2-1, R3-3, Pr-4, R7-3), (R1-8, R2-1, R3-4, Pr-1, R7-1), (R1-8, R2-1,R3-4, Pr-1, R7-2), (R1-8, R2-1, R3-4, Pr-1, R7-3), (R1-8, R2-1, R3-4,Pr-2, R7-1), (R1-8, R2-1, R3-4, Pr-2, R7-2), (R1-8, R2-1, R3-4, Pr-2,R7-3), (R1-8, R2-1, R3-4, Pr-3, R7-1), (R1-8, R2-1, R3-4, Pr-3, R7-2),(R1-8, R2-1, R3-4, Pr-3, R7-3), (R1-8, R2-1, R3-4, Pr-4, R7-1), (R1-8,R2-1, R3-4, Pr-4, R7-2), (R1-8, R2-1, R3-4, Pr-4, R7-3), (R1-8, R2-1,R3-5, Pr-1, R7-1), (R1-8, R2-1, R3-5, Pr-1, R7-2), (R1-8, R2-1, R3-5,Pr-1, R7-3), (R1-8, R2-1, R3-5, Pr-2, R7-1), (R1-8, R2-1, R3-5, Pr-2,R7-2), (R1-8, R2-1, R3-5, Pr-2, R7-3), (R1-8, R2-1, R3-5, Pr-3, R7-1),(R1-8, R2-1, R3-5, Pr-3, R7-2), (R1-8, R2-1, R3-5, Pr-3, R7-3), (R1-8,R2-1, R3-5, Pr-4, R7-1), (R1-8, R2-1, R3-5, Pr-4, R7-2), (R1-8, R2-1,R3-5, Pr-4, R7-3), (R1-8, R2-2, R3-1, Pr-1, R7-1), (R1-8, R2-2, R3-1,Pr-1, R7-2), (R1-8, R2-2, R3-1, Pr-1, R7-3), (R1-8, R2-2, R3-1, Pr-2,R7-1), (R1-8, R2-2, R3-1, Pr-2, R7-2), (R1-8, R2-2, R3-1, Pr-2, R7-3),(R1-8, R2-2, R3-1, Pr-3, R7-1), (R1-8, R2-2, R3-1, Pr-3, R7-2), (R1-8,R2-2, R3-1, Pr-3, R7-3), (R1-8, R2-2, R3-1, Pr-4, R7-1), (R1-8, R2-2,R3-1, Pr-4, R7-2), (R1-8, R2-2, R3-1, Pr-4, R7-3), (R1-8, R2-2, R3-2,Pr-1, R7-1), (R1-8, R2-2, R3-2, Pr-1, R7-2), (R1-8, R2-2, R3-2, Pr-1,R7-3), (R1-8, R2-2, R3-2, Pr-2, R7-1), (R1-8, R2-2, R3-2, Pr-2, R7-2),(R1-8, R2-2, R3-2, Pr-2, R7-3), (R1-8, R2-2, R3-2, Pr-3, R7-1), (R1-8,R2-2, R3-2, Pr-3, R7-2), (R1-8, R2-2, R3-2, Pr-3, R7-3), (R1-8, R2-2,R3-2, Pr-4, R7-1), (R1-8, R2-2, R3-2, Pr-4, R7-2), (R1-8, R2-2, R3-2,Pr-4, R7-3), (R1-8, R2-2, R3-3, Pr-1, R7-1), (R1-8, R2-2, R3-3, Pr-1,R7-2), (R1-8, R2-2, R3-3, Pr-1, R7-3), (R1-8, R2-2, R3-3, Pr-2, R7-1),(R1-8, R2-2, R3-3, Pr-2, R7-2), (R1-8, R2-2, R3-3, Pr-2, R7-3), (R1-8,R2-2, R3-3, Pr-3, R7-1), (R1-8, R2-2, R3-3, Pr-3, R7-2), (R1-8, R2-2,R3-3, Pr-3, R7-3), (R1-8, R2-2, R3-3, Pr-4, R7-1), (R1-8, R2-2, R3-3,Pr-4, R7-2), (R1-8, R2-2, R3-3, Pr-4, R7-3), (R1-8, R2-2, R3-4, Pr-1,R7-1), (R1-8, R2-2, R3-4, Pr-1, R7-2), (R1-8, R2-2, R3-4, Pr-1, R7-3),(R1-8, R2-2, R3-4, Pr-2, R7-1), (R1-8, R2-2, R3-4, Pr-2, R7-2), (R1-8,R2-2, R3-4, Pr-2, R7-3), (R1-8, R2-2, R3-4, Pr-3, R7-1), (R1-8, R2-2,R3-4, Pr-3, R7-2), (R1-8, R2-2, R3-4, Pr-3, R7-3), (R1-8, R2-2, R3-4,Pr-4, R7-1), (R1-8, R2-2, R3-4, Pr-4, R7-2), (R1-8, R2-2, R3-4, Pr-4,R7-3), (R1-8, R2-2, R3-5, Pr-1, R7-1), (R1-8, R2-2, R3-5, Pr-1, R7-2),(R1-8, R2-2, R3-5, Pr-1, R7-3), (R1-8, R2-2, R3-5, Pr-2, R7-1), (R1-8,R2-2, R3-5, Pr-2, R7-2), (R1-8, R2-2, R3-5, Pr-2, R7-3), (R1-8, R2-2,R3-5, Pr-3, R7-1), (R1-8, R2-2, R3-5, Pr-3, R7-2), (R1-8, R2-2, R3-5,Pr-3, R7-3), (R1-8, R2-2, R3-5, Pr-4, R7-1), (R1-8, R2-2, R3-5, Pr-4,R7-2), (R1-8, R2-2, R3-5, Pr-4, R7-3).

Compounds in which, in the formula (III), a combination of R^(1a),R^(2a), R^(3a), P^(R), as well as (R^(8a), R^(9a), R^(10a), and R^(11a))is as follows.

(R1-1, R2-1, R3-1, Pr-1, R9-1), (R1-1, R2-1, R3-1, Pr-1, R9-2), (R1-1,R2-1, R3-1, Pr-1, R9-3), (R-1, R2-1, R3-1, Pr-2, R9-1), (R1-1, R2-1,R3-1, Pr-2, R9-2), (R1-1, R2-1, R3-1, Pr-2, R9-3), (R1-1, R2-1, R3-1,Pr-3, R9-1), (R1-1, R2-1, R3-1, Pr-3, R9-2), (R1-1, R2-1, R3-1, Pr-3,R9-3), (R1-1, R2-1, R3-1, Pr-4, R9-1), (R1-1, R2-1, R3-1, Pr-4, R9-2),(R-1, R2-1, R3-1, Pr-4, R9-3), (R1-1, R2-1, R3-2, Pr-1, R9-1), (R1-1,R2-1, R3-2, Pr-1, R9-2), (R1-1, R2-1, R3-2, Pr-1, R9-3), (R1-1, R2-1,R3-2, Pr-2, R9-1), (R1-1, R2-1, R3-2, Pr-2, R9-2), (R1-1, R2-1, R3-2,Pr-2, R9-3), (R1-1, R2-1, R3-2, Pr-3, R9-1), (R1-1, R2-1, R3-2, Pr-3,R9-2), (R1-1, R2-1, R3-2, Pr-3, R9-3), (R1-1, R2-1, R3-2, Pr-4, R9-1),(R1-1, R2-1, R3-2, Pr-4, R9-2), (R1-1, R2-1, R3-2, Pr-4, R9-3), (R1-1,R2-1, R3-3, Pr-1, R9-1), (R1-1, R2-1, R3-3, Pr-1, R9-2), (R1-1, R2-1,R3-3, Pr-1, R9-3), (R1-1, R2-1, R3-3, Pr-2, R9-1), (R1-1, R2-1, R3-3,Pr-2, R9-2), (R1-1, R2-1, R3-3, Pr-2, R9-3), (R1-1, R2-1, R3-3, Pr-3,R9-1), (R1-1, R2-1, R3-3, Pr-3, R9-2), (R1-1, R2-1, R3-3, Pr-3, R9-3),(R1-1, R2-1, R3-3, Pr-4, R9-1), (R1-1, R2-1, R3-3, Pr-4, R9-2), (R1-1,R2-1, R3-3, Pr-4, R9-3), (R1-1, R2-1, R3-4, Pr-1, R9-1), (R1-1, R2-1,R3-4, Pr-1, R9-2), (R1-1, R2-1, R3-4, Pr-1, R9-3), (R1-1, R2-1, R3-4,Pr-2, R9-1), (R1-1, R2-1, R3-4, Pr-2, R9-2), (R1-1, R2-1, R3-4, Pr-2,R9-3), (R1-1, R2-1, R3-4, Pr-3, R9-1), (R1-1, R2-1, R3-4, Pr-3, R9-2),(R1-1, R2-1, R3-4, Pr-3, R9-3), (R1-1, R2-1, R3-4, Pr-4, R9-1), (R1-1,R2-1, R3-4, Pr-4, R9-2), (R1-1, R2-1, R3-4, Pr-4, R9-3), (R1-1, R2-1,R3-5, Pr-1, R9-1), (R1-1, R2-1, R3-5, Pr-1, R9-2), (R1-1, R2-1, R3-5,Pr-1, R9-3), (R1-1, R2-1, R3-5, Pr-2, R9-1), (R1-1, R2-1, R3-5, Pr-2,R9-2), (R1-1, R2-1, R3-5, Pr-2, R9-3), (R1-1, R2-1, R3-5, Pr-3, R9-1),(R1-1, R2-1, R3-5, Pr-3, R9-2), (R1-1, R2-1, R3-5, Pr-3, R9-3), (R1-1,R2-1, R3-5, Pr-4, R9-1), (R1-1, R2-1, R3-5, Pr-4, R9-2), (R1-1, R2-1,R3-5, Pr-4, R9-3), (R1-1, R2-2, R3-1, Pr-1, R9-1), (R1-1, R2-2, R3-1,Pr-1, R9-2), (R1-1, R2-2, R3-1, Pr-1, R9-3), (R1-1, R2-2, R3-1, Pr-2,R9-1), (R1-1, R2-2, R3-1, Pr-2, R9-2), (R1-1, R2-2, R3-1, Pr-2, R9-3),(R1-1, R2-2, R3-1, Pr-3, R9-1), (R1-1, R2-2, R3-1, Pr-3, R9-2), (R1-1,R2-2, R3-1, Pr-3, R9-3), (R1-1, R2-2, R3-1, Pr-4, R9-1), (R1-1, R2-2,R3-1, Pr-4, R9-2), (R1-1, R2-2, R3-1, Pr-4, R9-3), (R1-1, R2-2, R3-2,Pr-1, R9-1), (R1-1, R2-2, R3-2, Pr-1, R9-2), (R1-1, R2-2, R3-2, Pr-1,R9-3), (R1-1, R2-2, R3-2, Pr-2, R9-1), (R1-1, R2-2, R3-2, Pr-2, R9-2),(R1-1, R2-2, R3-2, Pr-2, R9-3), (R1-1, R2-2, R3-2, Pr-3, R9-1), (R1-1,R2-2, R3-2, Pr-3, R9-2), (R1-1, R2-2, R3-2, Pr-3, R9-3), (R1-1, R2-2,R3-2, Pr-4, R9-1), (R1-1, R2-2, R3-2, Pr-4, R9-2), (R1-1, R2-2, R3-2,Pr-4, R9-3), (R1-1, R2-2, R3-3, Pr-1, R9-1), (R1-1, R2-2, R3-3, Pr-1,R9-2), (R1-1, R2-2, R3-3, Pr-1, R9-3), (R1-1, R2-2, R3-3, Pr-2, R9-1),(R1-1, R2-2, R3-3, Pr-2, R9-2), (R1-1, R2-2, R3-3, Pr-2, R9-3), (R1-1,R2-2, R3-3, Pr-3, R9-1), (R1-1, R2-2, R3-3, Pr-3, R9-2), (R1-1, R2-2,R3-3, Pr-3, R9-3), (R1-1, R2-2, R3-3, Pr-4, R9-1), (R1-1, R2-2, R3-3,Pr-4, R9-2), (R1-1, R2-2, R3-3, Pr-4, R9-3), (R1-1, R2-2, R3-4, Pr-1,R9-1), (R1-1, R2-2, R3-4, Pr-1, R9-2), (R1-1, R2-2, R3-4, Pr-1, R9-3),(R1-1, R2-2, R3-4, Pr-2, R9-1), (R1-1, R2-2, R3-4, Pr-2, R9-2), (R1-1,R2-2, R3-4, Pr-2, R9-3), (R1-1, R2-2, R3-4, Pr-3, R9-1), (R1-1, R2-2,R3-4, Pr-3, R9-2), (R1-1, R2-2, R3-4, Pr-3, R9-3), (R1-1, R2-2, R3-4,Pr-4, R9-1), (R1-1, R2-2, R3-4, Pr-4, R9-2), (R1-1, R2-2, R3-4, Pr-4,R9-3), (R1-1, R2-2, R3-5, Pr-1, R9-1), (R1-1, R2-2, R3-5, Pr-1, R9-2),(R1-1, R2-2, R3-5, Pr-1, R9-3), (R1-1, R2-2, R3-5, Pr-2, R9-1), (R1-1,R2-2, R3-5, Pr-2, R9-2), (R1-1, R2-2, R3-5, Pr-2, R9-3), (R1-1, R2-2,R3-5, Pr-3, R9-1), (R1-1, R2-2, R3-5, Pr-3, R9-2), (R1-1, R2-2, R3-5,Pr-3, R9-3), (R1-1, R2-2, R3-5, Pr-4, R9-1), (R1-1, R2-2, R3-5, Pr-4,R9-2), (R1-1, R2-2, R3-5, Pr-4, R9-3),

(R1-2, R2-1, R3-1, Pr-1, R9-1), (R1-2, R2-1, R3-1, Pr-1, R9-2), (R1-2,R2-1, R3-1, Pr-1, R9-3), (R1-2, R2-1, R3-1, Pr-2, R9-1), (R1-2, R2-1,R3-1, Pr-2, R9-2), (R1-2, R2-1, R3-1, Pr-2, R9-3), (R1-2, R2-1, R3-1,Pr-3, R9-1), (R1-2, R2-1, R3-1, Pr-3, R9- 2), (R1-2, R2-1, R3-1, Pr-3,R9-3), (R1-2, R2-1, R3-1, Pr-4, R9-1), (R1-2, R2-1, R3-1, Pr-4, R9-2),(R1-2, R2-1, R3-1, Pr-4, R9-3), (R1-2, R2-1, R3-2, Pr-1, R9-1), (R1-2,R2-1, R3-2, Pr-1, R9-2), (R1-2, R2-1, R3-2, Pr-1, R9-3), (R1-2, R2-1,R3-2, Pr-2, R9-1), (R1-2, R2-1, R3-2, Pr-2, R9-2), (R1-2, R2-1, R3-2,Pr-2, R9-3), (R1-2, R2-1, R3-2, Pr-3, R9-1), (R1-2, R2-1, R3-2, Pr-3,R9-2), (R1-2, R2-1, R3-2, Pr-3, R9-3), (R1-2, R2-1, R3-2, Pr-4, R9-1),(R1-2, R2-1, R3-2, Pr-4, R9-2), (R1-2, R2-1, R3-2, Pr-4, R9-3), (R1-2,R2-1, R3-3, Pr-1, R9-1), (R1-2, R2-1, R3-3, Pr-1, R9-2), (R1-2, R2-1,R3-3, Pr-1, R9-3), (R1-2, R2-1, R3-3, Pr-2, R9-1), (R1-2, R2-1, R3-3,Pr-2, R9-2), (R1-2, R2-1, R3-3, Pr-2, R9-3), (R1-2, R2-1, R3-3, Pr-3,R9-1), (R1-2, R2-1, R3-3, Pr-3, R9-2), (R1-2, R2-1, R3-3, Pr-3, R9-3),(R1-2, R2-1, R3-3, Pr-4, R9-1), (R1-2, R2-1, R3-3, Pr-4, R9-2), (R1-2,R2-1, R3-3, Pr-4, R9-3), (R1-2, R2-1, R3-4, Pr-1, R9-1), (R1-2, R2-1,R3-4, Pr-1, R9-2), (R1-2, R2-1, R3-4, Pr-1, R9-3), (R1-2, R2-1, R3-4,Pr-2, R9-1), (R1-2, R2-1, R3-4, Pr-2, R9-2), (R1-2, R2-1, R3-4, Pr-2,R9-3), (R1-2, R2-1, R3-4, Pr-3, R9-1), (R1-2, R2-1, R3-4, Pr-3, R9-2),(R1-2, R2-1, R3-4, Pr-3, R9-3), (R1-2, R2-1, R3-4, Pr-4, R9-1), (R1-2,R2-1, R3-4, Pr-4, R9-2), (R1-2, R2-1, R3-4, Pr-4, R9-3), (R1-2, R2-1,R3-5, Pr-1, R9-1), (R1-2, R2-1, R3-5, Pr-1, R9-2), (R1-2, R2-1, R3-5,Pr-1, R9-3), (R1-2, R2-1, R3-5, Pr-2, R9-1), (R1-2, R2-1, R3-5, Pr-2,R9-2), (R1-2, R2-1, R3-5, Pr-2, R9-3), (R1-2, R2-1, R3-5, Pr-3, R9-1),(R1-2, R2-1, R3-5, Pr-3, R9-2), (R1-2, R2-1, R3-5, Pr-3, R9-3), (R1-2,R2-1, R3-5, Pr-4, R9-1), (R1-2, R2-1, R3-5, Pr-4, R9-2), (R1-2, R2-1,R3-5, Pr-4, R9-3), (R1-2, R2-2, R3-1, Pr-1, R9-1), (R1-2, R2-2, R3-1,Pr-1, R9-2), (R1-2, R2-2, R3-1, Pr-1, R9-3), (R1-2, R2-2, R3-1, Pr-2,R9-1), (R1-2, R2-2, R3-1, Pr-2, R9-2), (R1-2, R2-2, R3-1, Pr-2, R9-3),(R1-2, R2-2, R3-1, Pr-3, R9-1), (R1-2, R2-2, R3-1, Pr-3, R9-2), (R1-2,R2-2, R3-1, Pr-3, R9-3), (R1-2, R2-2, R3-1, Pr-4, R9-1), (R1-2, R2-2,R3-1, Pr-4, R9-2), (R1-2, R2-2, R3-1, Pr-4, R9-3), (R1-2, R2-2, R3-2,Pr-1, R9-1), (R1-2, R2-2, R3-2, Pr-1, R9-2), (R1-2, R2-2, R3-2, Pr-1,R9-3), (R1-2, R2-2, R3-2, Pr-2, R9-1), (R1-2, R2-2, R3-2, Pr-2, R9-2),(R1-2, R2-2, R3-2, Pr-2, R9-3), (R1-2, R2-2, R3-2, Pr-3, R9-1), (R1-2,R2-2, R3-2, Pr-3, R9-2), (R1-2, R2-2, R3-2, Pr-3, R9-3), (R1-2, R2-2,R3-2, Pr-4, R9-1), (R1-2, R2-2, R3-2, Pr-4, R9-2), (R-2, R2-2, R3-2,Pr-4, R9-3), (R1-2, R2-2, R3-3, Pr-1, R9-1), (R1-2, R2-2, R3-3, Pr-1,R9-2), (R1-2, R2-2, R3-3, Pr-1, R9-3), (R1-2, R2-2, R3-3, Pr-2, R9-1),(R-2, R2-2, R3-3, Pr-2, R9-2), (R1-2, R2-2, R3-3, Pr-2, R9-3), (R1-2,R2-2, R3-3, Pr-3, R9-1), (R-2, R2-2, R3-3, Pr-3, R9-2), (R1-2, R2-2,R3-3, Pr-3, R9-3), (R1-2, R2-2, R3-3, Pr-4, R9-1), (R1-2, R2-2, R3-3,Pr-4, R9-2), (R1-2, R2-2, R3-3, Pr-4, R9-3), (R1-2, R2-2, R3-4, Pr-1,R9-1), (R1-2, R2-2, R3-4, Pr-1, R9-2), (R1-2, R2-2, R3-4, Pr-1, R9-3),(R1-2, R2-2, R3-4, Pr-2, R9-1), (R1-2, R2-2, R3-4, Pr-2, R9-2), (R1-2,R2-2, R3-4, Pr-2, R9-3), (R1-2, R2-2, R3-4, Pr-3, R9-1), (R1-2, R2-2,R3-4, Pr-3, R9-2), (R1-2, R2-2, R3-4, Pr-3, R9-3), (R1-2, R2-2, R3-4,Pr-4, R9-1), (R1-2, R2-2, R3-4, Pr-4, R9-2), (R-2, R2-2, R3-4, Pr-4,R9-3), (R1-2, R2-2, R3-5, Pr-1, R9-1), (R1-2, R2-2, R3-5, Pr-1, R9-2),(R1-2, R2-2, R3-5, Pr-1, R9-3), (R1-2, R2-2, R3-5, Pr-2, R9-1), (R-2,R2-2, R3-5, Pr-2, R9-2), (R1-2, R2-2, R3-5, Pr-2, R9-3), (R1-2, R2-2,R3-5, Pr-3, R9-1), (R-2, R2-2, R3-5, Pr-3, R9-2), (R1-2, R2-2, R3-5,Pr-3, R9-3), (R1-2, R2-2, R3-5, Pr-4, R9-1), (R1-2, R2-2, R3-5, Pr-4,R9-2), (R1-2, R2-2, R3-5, Pr-4, R9-3),

(R1-3, R2-1, R3-1, Pr-1, R9-1), (R1-3, R2-1, R3-1, Pr-1, R9-2), (R1-3,R2-1, R3-1, Pr-1, R9-3), (R1-3, R2-1, R3-1, Pr-2, R9-1), (R1-3, R2-1,R3-1, Pr-2, R9-2), (R1-3, R2-1, R3-1, Pr-2, R9-3), (R1-3, R2-1, R3-1,Pr-3, R9-1), (R1-3, R2-1, R3-1, Pr-3, R9- 2), (R1-3, R2-1, R3-1, Pr-3,R9-3), (R1-3, R2-1, R3-1, Pr-4, R9-1), (R1-3, R2-1, R3-1, Pr-4, R9-2),(R1-3, R2-1, R3-1, Pr-4, R9-3), (R1-3, R2-1, R3-2, Pr-1, R9-1), (R1-3,R2-1, R3-2, Pr-1, R9-2), (R1-3, R2-1, R3-2, Pr-1, R9-3), (R1-3, R2-1,R3-2, Pr-2, R9-1), (R1-3, R2-1, R3-2, Pr-2, R9-2), (R1-3, R2-1, R3-2,Pr-2, R9-3), (R1-3, R2-1, R3-2, Pr-3, R9-1), (R1-3, R2-1, R3-2, Pr-3,R9-2), (R1-3, R2-1, R3-2, Pr-3, R9-3), (R1-3, R2-1, R3-2, Pr-4, R9-1),(R1-3, R2-1, R3-2, Pr-4, R9-2), (R1-3, R2-1, R3-2, Pr-4, R9-3), (R1-3,R2-1, R3-3, Pr-1, R9-1), (R1-3, R2-1, R3-3, Pr-1, R9-2), (R1-3, R2-1,R3-3, Pr-1, R9-3), (R1-3, R2-1, R3-3, Pr-2, R9-1), (R1-3, R2-1, R3-3,Pr-2, R9-2), (R1-3, R2-1, R3-3, Pr-2, R9-3), (R1-3, R2-1, R3-3, Pr-3,R9-1), (R1-3, R2-1, R3-3, Pr-3, R9-2), (R1-3, R2-1, R3-3, Pr-3, R9-3),(R1-3, R2-1, R3-3, Pr-4, R9-1), (R1-3, R2-1, R3-3, Pr-4, R9-2), (R1-3,R2-1, R3-3, Pr-4, R9-3), (R1-3, R2-1, R3-4, Pr-1, R9-1), (R1-3, R2-1,R3-4, Pr-1, R9-2), (R1-3, R2-1, R3-4, Pr-1, R9-3), (R1-3, R2-1, R3-4,Pr-2, R9-1), (R1-3, R2-1, R3-4, Pr-2, R9-2), (R1-3, R2-1, R3-4, Pr-2,R9-3), (R1-3, R2-1, R3-4, Pr-3, R9-1), (R1-3, R2-1, R3-4, Pr-3, R9-2),(R1-3, R2-1, R3-4, Pr-3, R9-3), (R1-3, R2-1, R3-4, Pr-4, R9-1), (R1-3,R2-1, R3-4, Pr-4, R9-2), (R1-3, R2-1, R3-4, Pr-4, R9-3), (R1-3, R2-1,R3-5, Pr-1, R9-1), (R1-3, R2-1, R3-5, Pr-1, R9-2), (R1-3, R2-1, R3-5,Pr-1, R9-3), (R1-3, R2-1, R3-5, Pr-2, R9-1), (R1-3, R2-1, R3-5, Pr-2,R9-2), (R1-3, R2-1, R3-5, Pr-2, R9-3), (R1-3, R2-1, R3-5, Pr-3, R9-1),(R1-3, R2-1, R3-5, Pr-3, R9-2), (R1-3, R2-1, R3-5, Pr-3, R9-3), (R1-3,R2-1, R3-5, Pr-4, R9-1), (R1-3, R2-1, R3-5, Pr-4, R9-2), (R1-3, R2-1,R3-5, Pr-4, R9-3), (R1-3, R2-2, R3-1, Pr-1, R9-1), (R1-3, R2-2, R3-1,Pr-1, R9-2), (R1-3, R2-2, R3-1, Pr-1, R9-3), (R1-3, R2-2, R3-1, Pr-2,R9-1), (R1-3, R2-2, R3-1, Pr-2, R9-2), (R1-3, R2-2, R3-1, Pr-2, R9-3),(R1-3, R2-2, R3-1, Pr-3, R9-1), (R1-3, R2-2, R3-1, Pr-3, R9-2), (R1-3,R2-2, R3-1, Pr-3, R9-3), (R1-3, R2-2, R3-1, Pr-4, R9-1), (R1-3, R2-2,R3-1, Pr-4, R9-2), (R1-3, R2-2, R3-1, Pr-4, R9-3), (R1-3, R2-2, R3-2,Pr-1, R9-1), (R1-3, R2-2, R3-2, Pr-1, R9-2), (R1-3, R2-2, R3-2, Pr-1,R9-3), (R1-3, R2-2, R3-2, Pr-2, R9-1), (R1-3, R2-2, R3-2, Pr-2, R9-2),(R1-3, R2-2, R3-2, Pr-2, R9-3), (R1-3, R2-2, R3-2, Pr-3, R9-1), (R1-3,R2-2, R3-2, Pr-3, R9-2), (R1-3, R2-2, R3-2, Pr-3, R9-3), (R1-3, R2-2,R3-2, Pr-4, R9-1), (R1-3, R2-2, R3-2, Pr-4, R9-2), (R1-3, R2-2, R3-2,Pr-4, R9-3), (R1-3, R2-2, R3-3, Pr-1, R9-1), (R1-3, R2-2, R3-3, Pr-1,R9-2), (R1-3, R2-2, R3-3, Pr-1, R9-3), (R1-3, R2-2, R3-3, Pr-2, R9-1),(R1-3, R2-2, R3-3, Pr-2, R9-2), (R1-3, R2-2, R3-3, Pr-2, R9-3), (R1-3,R2-2, R3-3, Pr-3, R9-1), (R1-3, R2-2, R3-3, Pr-3, R9-2), (R-3, R2-2,R3-3, Pr-3, R9-3), (R1-3, R2-2, R3-3, Pr-4, R9-1), (R1-3, R2-2, R3-3,Pr-4, R9-2), (R1-3, R2-2, R3-3, Pr-4, R9-3), (R1-3, R2-2, R3-4, Pr-1,R9-1), (R-3, R2-2, R3-4, Pr-1, R9-2), (R1-3, R2-2, R3-4, Pr-1, R9-3),(R1-3, R2-2, R3-4, Pr-2, R9-1), (R-3, R2-2, R3-4, Pr-2, R9-2), (R1-3,R2-2, R3-4, Pr-2, R9-3), (R1-3, R2-2, R3-4, Pr-3, R9-1), (R1-3, R2-2,R3-4, Pr-3, R9-2), (R1-3, R2-2, R3-4, Pr-3, R9-3), (R1-3, R2-2, R3-4,Pr-4, R9-1), (R1-3, R2-2, R3-4, Pr-4, R9-2), (R1-3, R2-2, R3-4, Pr-4,R9-3), (R1-3, R2-2, R3-5, Pr-1, R9-1), (R1-3, R2-2, R3-5, Pr-1, R9-2),(R1-3, R2-2, R3-5, Pr-1, R9-3), (R1-3, R2-2, R3-5, Pr-2, R9-1), (R1-3,R2-2, R3-5, Pr-2, R9-2), (R1-3, R2-2, R3-5, Pr-2, R9-3), (R1-3, R2-2,R3-5, Pr-3, R9-1), (R1-3, R2-2, R3-5, Pr-3, R9-2), (R-3, R2-2, R3-5,Pr-3, R9-3), (R1-3, R2-2, R3-5, Pr-4, R9-1), (R1-3, R2-2, R3-5, Pr-4,R9-2), (R1-3, R2-2, R3-5, Pr-4, R9-3),

(R1-4, R2-1, R3-1, Pr-1, R9-1), (R1-4, R2-1, R3-1, Pr-1, R9-2), (R1-4,R2-1, R3-1, Pr-1, R9-3), (R1-4, R2-1, R3-1, Pr-2, R9-1), (R1-4, R2-1,R3-1, Pr-2, R9-2), (R1-4, R2-1, R3-1, Pr-2, R9-3), (R1-4, R2-1, R3-1,Pr-3, R9-1), (R1-4, R2-1, R3-1, Pr-3, R9- 2), (R1-4, R2-1, R3-1, Pr-3,R9-3), (R1-4, R2-1, R3-1, Pr-4, R9-1), (R1-4, R2-1, R3-1, Pr-4, R9-2),(R1-4, R2-1, R3-1, Pr-4, R9-3), (R1-4, R2-1, R3-2, Pr-1, R9-1), (R1-4,R2-1, R3-2, Pr-1, R9-2), (R1-4, R2-1, R3-2, Pr-1, R9-3), (R1-4, R2-1,R3-2, Pr-2, R9-1), (R1-4, R2-1, R3-2, Pr-2, R9-2), (R1-4, R2-1, R3-2,Pr-2, R9-3), (R1-4, R2-1, R3-2, Pr-3, R9-1), (R1-4, R2-1, R3-2, Pr-3,R9-2), (R1-4, R2-1, R3-2, Pr-3, R9-3), (R1-4, R2-1, R3-2, Pr-4, R9-1),(R1-4, R2-1, R3-2, Pr-4, R9-2), (R1-4, R2-1, R3-2, Pr-4, R9-3), (R1-4,R2-1, R3-3, Pr-1, R9-1), (R1-4, R2-1, R3-3, Pr-1, R9-2), (R1-4, R2-1,R3-3, Pr-1, R9-3), (R1-4, R2-1, R3-3, Pr-2, R9-1), (R1-4, R2-1, R3-3,Pr-2, R9-2), (R1-4, R2-1, R3-3, Pr-2, R9-3), (R1-4, R2-1, R3-3, Pr-3,R9-1), (R1-4, R2-1, R3-3, Pr-3, R9-2), (R1-4, R2-1, R3-3, Pr-3, R9-3),(R1-4, R2-1, R3-3, Pr-4, R9-1), (R1-4, R2-1, R3-3, Pr-4, R9-2), (R1-4,R2-1, R3-3, Pr-4, R9-3), (R1-4, R2-1, R3-4, Pr-1, R9-1), (R1-4, R2-1,R3-4, Pr-1, R9-2), (R1-4, R2-1, R3-4, Pr-1, R9-3), (R1-4, R2-1, R3-4,Pr-2, R9-1), (R1-4, R2-1, R3-4, Pr-2, R9-2), (R1-4, R2-1, R3-4, Pr-2,R9-3), (R1-4, R2-1, R3-4, Pr-3, R9-1), (R1-4, R2-1, R3-4, Pr-3, R9-2),(R1-4, R2-1, R3-4, Pr-3, R9-3), (R1-4, R2-1, R3-4, Pr-4, R9-1), (R1-4,R2-1, R3-4, Pr-4, R9-2), (R1-4, R2-1, R3-4, Pr-4, R9-3), (R1-4, R2-1,R3-5, Pr-1, R9-1), (R1-4, R2-1, R3-5, Pr-1, R9-2), (R1-4, R2-1, R3-5,Pr-1, R9-3), (R1-4, R2-1, R3-5, Pr-2, R9-1), (R1-4, R2-1, R3-5, Pr-2,R9-2), (R1-4, R2-1, R3-5, Pr-2, R9-3), (R1-4, R2-1, R3-5, Pr-3, R9-1),(R1-4, R2-1, R3-5, Pr-3, R9-2), (R1-4, R2-1, R3-5, Pr-3, R9-3), (R1-4,R2-1, R3-5, Pr-4, R9-1), (R1-4, R2-1, R3-5, Pr-4, R9-2), (R1-4, R2-1,R3-5, Pr-4, R9-3), (R1-4, R2-2, R3-1, Pr-1, R9-1), (R1-4, R2-2, R3-1,Pr-1, R9-2), (R1-4, R2-2, R3-1, Pr-1, R9-3), (R1-4, R2-2, R3-1, Pr-2,R9-1), (R1-4, R2-2, R3-1, Pr-2, R9-2), (R1-4, R2-2, R3-1, Pr-2, R9-3),(R1-4, R2-2, R3-1, Pr-3, R9-1), (R1-4, R2-2, R3-1, Pr-3, R9-2), (R1-4,R2-2, R3-1, Pr-3, R9-3), (R1-4, R2-2, R3-1, Pr-4, R9-1), (R1-4, R2-2,R3-1, Pr-4, R9-2), (R1-4, R2-2, R3-1, Pr-4, R9-3), (R1-4, R2-2, R3-2,Pr-1, R9-1), (R1-4, R2-2, R3-2, Pr-1, R9-2), (R1-4, R2-2, R3-2, Pr-1,R9-3), (R1-4, R2-2, R3-2, Pr-2, R9-1), (R1-4, R2-2, R3-2, Pr-2, R9-2),(R1-4, R2-2, R3-2, Pr-2, R9-3), (R1-4, R2-2, R3-2, Pr-3, R9-1), (R1-4,R2-2, R3-2, Pr-3, R9-2), (R1-4, R2-2, R3-2, Pr-3, R9-3), (R1-4, R2-2,R3-2, Pr-4, R9-1), (R1-4, R2-2, R3-2, Pr-4, R9-2), (R1-4, R2-2, R3-2,Pr-4, R9-3), (R1-4, R2-2, R3-3, Pr-1, R9-1), (R1-4, R2-2, R3-3, Pr-1,R9-2), (R1-4, R2-2, R3-3, Pr-1, R9-3), (R1-4, R2-2, R3-3, Pr-2, R9-1),(R1-4, R2-2, R3-3, Pr-2, R9-2), (R1-4, R2-2, R3-3, Pr-2, R9-3), (R1-4,R2-2, R3-3, Pr-3, R9-1), (R1-4, R2-2, R3-3, Pr-3, R9-2), (R1-4, R2-2,R3-3, Pr-3, R9-3), (R1-4, R2-2, R3-3, Pr-4, R9-1), (R1-4, R2-2, R3-3,Pr-4, R9-2), (R1-4, R2-2, R3-3, Pr-4, R9-3), (R1-4, R2-2, R3-4, Pr-1,R9-1), (R1-4, R2-2, R3-4, Pr-1, R9-2), (R1-4, R2-2, R3-4, Pr-1, R9-3),(R1-4, R2-2, R3-4, Pr-2, R9-1), (R1-4, R2-2, R3-4, Pr-2, R9-2), (R1-4,R2-2, R3-4, Pr-2, R9-3), (R1-4, R2-2, R3-4, Pr-3, R9-1), (R1-4, R2-2,R3-4, Pr-3, R9-2), (R1-4, R2-2, R3-4, Pr-3, R9-3), (R1-4, R2-2, R3-4,Pr-4, R9-1), (R1-4, R2-2, R3-4, Pr-4, R9-2), (R1-4, R2-2, R3-4, Pr-4,R9-3), (R1-4, R2-2, R3-5, Pr-1, R9-1), (R1-4, R2-2, R3-5, Pr-1, R9-2),(R1-4, R2-2, R3-5, Pr-1, R9-3), (R1-4, R2-2, R3-5, Pr-2, R9-1), (R1-4,R2-2, R3-5, Pr-2, R9-2), (R1-4, R2-2, R3-5, Pr-2, R9-3), (R1-4, R2-2,R3-5, Pr-3, R9-1), (R1-4, R2-2, R3-5, Pr-3, R9-2), (R1-4, R2-2, R3-5,Pr-3, R9-3), (R1-4, R2-2, R3-5, Pr-4, R9-1), (R1-4, R2-2, R3-5, Pr-4,R9-2), (R1-4, R2-2, R3-5, Pr-4, R9-3),

(R1-5, R2-1, R3-1, Pr-1, R9-1), (R1-5, R2-1, R3-1, Pr-1, R9-2), (R1-5,R2-1, R3-1, Pr-1, R9-3), (R1-5, R2-1, R3-1, Pr-2, R9-1), (R1-5, R2-1,R3-1, Pr-2, R9-2), (R1-5, R2-1, R3-1, Pr-2, R9-3), (R1-5, R2-1, R3-1,Pr-3, R9-1), (R1-5, R2-1, R3-1, Pr-3, R9- 2), (R1-5, R2-1, R3-1, Pr-3,R9-3), (R1-5, R2-1, R3-1, Pr-4, R9-1), (R1-5, R2-1, R3-1, Pr-4, R9-2),(R1-5, R2-1, R3-1, Pr-4, R9-3), (R1-5, R2-1, R3-2, Pr-1, R9-1), (R1-5,R2-1, R3-2, Pr-1, R9-2), (R1-5, R2-1, R3-2, Pr-1, R9-3), (R1-5, R2-1,R3-2, Pr-2, R9-1), (R1-5, R2-1, R3-2, Pr-2, R9-2), (R1-5, R2-1, R3-2,Pr-2, R9-3), (R1-5, R2-1, R3-2, Pr-3, R9-1), (R1-5, R2-1, R3-2, Pr-3,R9-2), (R1-5, R2-1, R3-2, Pr-3, R9-3), (R1-5, R2-1, R3-2, Pr-4, R9-1),(R1-5, R2-1, R3-2, Pr-4, R9-2), (R1-5, R2-1, R3-2, Pr-4, R9-3), (R1-5,R2-1, R3-3, Pr-1, R9-1), (R1-5, R2-1, R3-3, Pr-1, R9-2), (R1-5, R2-1,R3-3, Pr-1, R9-3), (R1-5, R2-1, R3-3, Pr-2, R9-1), (R1-5, R2-1, R3-3,Pr-2, R9-2), (R1-5, R2-1, R3-3, Pr-2, R9-3), (R1-5, R2-1, R3-3, Pr-3,R9-1), (R1-5, R2-1, R3-3, Pr-3, R9-2), (R1-5, R2-1, R3-3, Pr-3, R9-3),(R1-5, R2-1, R3-3, Pr-4, R9-1), (R1-5, R2-1, R3-3, Pr-4, R9-2), (R1-5,R2-1, R3-3, Pr-4, R9-3), (R1-5, R2-1, R3-4, Pr-1, R9-1), (R1-5, R2-1,R3-4, Pr-1, R9-2), (R1-5, R2-1, R3-4, Pr-1, R9-3), (R1-5, R2-1, R3-4,Pr-2, R9-1), (R1-5, R2-1, R3-4, Pr-2, R9-2), (R1-5, R2-1, R3-4, Pr-2,R9-3), (R1-5, R2-1, R3-4, Pr-3, R9-1), (R1-5, R2-1, R3-4, Pr-3, R9-2),(R1-5, R2-1, R3-4, Pr-3, R9-3), (R1-5, R2-1, R3-4, Pr-4, R9-1), (R1-5,R2-1, R3-4, Pr-4, R9-2), (R1-5, R2-1, R3-4, Pr-4, R9-3), (R1-5, R2-1,R3-5, Pr-1, R9-1), (R1-5, R2-1, R3-5, Pr-1, R9-2), (R1-5, R2-1, R3-5,Pr-1, R9-3), (R1-5, R2-1, R3-5, Pr-2, R9-1), (R1-5, R2-1, R3-5, Pr-2,R9-2), (R1-5, R2-1, R3-5, Pr-2, R9-3), (R1-5, R2-1, R3-5, Pr-3, R9-1),(R1-5, R2-1, R3-5, Pr-3, R9-2), (R1-5, R2-1, R3-5, Pr-3, R9-3), (R1-5,R2-1, R3-5, Pr-4, R9-1), (R1-5, R2-1, R3-5, Pr-4, R9-2), (R1-5, R2-1,R3-5, Pr-4, R9-3), (R1-5, R2-2, R3-1, Pr-1, R9-1), (R1-5, R2-2, R3-1,Pr-1, R9-2), (R1-5, R2-2, R3-1, Pr-1, R9-3), (R1-5, R2-2, R3-1, Pr-2,R9-1), (R1-5, R2-2, R3-1, Pr-2, R9-2), (R1-5, R2-2, R3-1, Pr-2, R9-3),(R1-5, R2-2, R3-1, Pr-3, R9-1), (R1-5, R2-2, R3-1, Pr-3, R9-2), (R1-5,R2-2, R3-1, Pr-3, R9-3), (R1-5, R2-2, R3-1, Pr-4, R9-1), (R1-5, R2-2,R3-1, Pr-4, R9-2), (R1-5, R2-2, R3-1, Pr-4, R9-3), (R1-5, R2-2, R3-2,Pr-1, R9-1), (R1-5, R2-2, R3-2, Pr-1, R9-2), (R1-5, R2-2, R3-2, Pr-1,R9-3), (R1-5, R2-2, R3-2, Pr-2, R9-1), (R1-5, R2-2, R3-2, Pr-2, R9-2),(R1-5, R2-2, R3-2, Pr-2, R9-3), (R1-5, R2-2, R3-2, Pr-3, R9-1), (R1-5,R2-2, R3-2, Pr-3, R9-2), (R1-5, R2-2, R3-2, Pr-3, R9-3), (R1-5, R2-2,R3-2, Pr-4, R9-1), (R1-5, R2-2, R3-2, Pr-4, R9-2), (R1-5, R2-2, R3-2,Pr-4, R9-3), (R1-5, R2-2, R3-3, Pr-1, R9-1), (R1-5, R2-2, R3-3, Pr-1,R9-2), (R1-5, R2-2, R3-3, Pr-1, R9-3), (R1-5, R2-2, R3-3, Pr-2, R9-1),(R1-5, R2-2, R3-3, Pr-2, R9-2), (R1-5, R2-2, R3-3, Pr-2, R9-3), (R1-5,R2-2, R3-3, Pr-3, R9-1), (R1-5, R2-2, R3-3, Pr-3, R9-2), (R1-5, R2-2,R3-3, Pr-3, R9-3), (R1-5, R2-2, R3-3, Pr-4, R9-1), (R1-5, R2-2, R3-3,Pr-4, R9-2), (R1-5, R2-2, R3-3, Pr-4, R9-3), (R1-5, R2-2, R3-4, Pr-1,R9-1), (R1-5, R2-2, R3-4, Pr-1, R9-2), (R1-5, R2-2, R3-4, Pr-1, R9-3),(R1-5, R2-2, R3-4, Pr-2, R9-1), (R-5, R2-2, R3-4, Pr-2, R9-2), (R1-5,R2-2, R3-4, Pr-2, R9-3), (R1-5, R2-2, R3-4, Pr-3, R9-1), (R1-5, R2-2,R3-4, Pr-3, R9-2), (R1-5, R2-2, R3-4, Pr-3, R9-3), (R1-5, R2-2, R3-4,Pr-4, R9-1), (R1-5, R2-2, R3-4, Pr-4, R9-2), (R1-5, R2-2, R3-4, Pr-4,R9-3), (R1-5, R2-2, R3-5, Pr-1, R9-1), (R1-5, R2-2, R3-5, Pr-1, R9-2),(R1-5, R2-2, R3-5, Pr-1, R9-3), (R1-5, R2-2, R3-5, Pr-2, R9-1), (R1-5,R2-2, R3-5, Pr-2, R9-2), (R1-5, R2-2, R3-5, Pr-2, R9-3), (R1-5, R2-2,R3-5, Pr-3, R9-1), (R1-5, R2-2, R3-5, Pr-3, R9-2), (R-5, R2-2, R3-5,Pr-3, R9-3), (R1-5, R2-2, R3-5, Pr-4, R9-1), (R1-5, R2-2, R3-5, Pr-4,R9-2), (R1-5, R2-2, R3-5, Pr-4, R9-3),

(R1-6, R2-1, R3-1, Pr-1, R9-1), (R-6, R2-1, R3-1, Pr-1, R9-2), (R1-6,R2-1, R3-1, Pr-1, R9-3), (R1-6, R2-1, R3-1, Pr-2, R9-1), (R1-6, R2-1,R3-1, Pr-2, R9-2), (R1-6, R2-1, R3-1, Pr-2, R9-3), (R1-6, R2-1, R3-1,Pr-3, R9-1), (R1-6, R2-1, R3-1, Pr-3, R9- 2), (R1-6, R2-1, R3-1, Pr-3,R9-3), (R1-6, R2-1, R3-1, Pr-4, R9-1), (R1-6, R2-1, R3-1, Pr-4, R9-2),(R1-6, R2-1, R3-1, Pr-4, R9-3), (R1-6, R2-1, R3-2, Pr-1, R9-1), (R1-6,R2-1, R3-2, Pr-1, R9-2), (R1-6, R2-1, R3-2, Pr-1, R9-3), (R1-6, R2-1,R3-2, Pr-2, R9-1), (R1-6, R2-1, R3-2, Pr-2, R9-2), (R1-6, R2-1, R3-2,Pr-2, R9-3), (R1-6, R2-1, R3-2, Pr-3, R9-1), (R1-6, R2-1, R3-2, Pr-3,R9-2), (R1-6, R2-1, R3-2, Pr-3, R9-3), (R1-6, R2-1, R3-2, Pr-4, R9-1),(R1-6, R2-1, R3-2, Pr-4, R9-2), (R1-6, R2-1, R3-2, Pr-4, R9-3), (R1-6,R2-1, R3-3, Pr-1, R9-1), (R1-6, R2-1, R3-3, Pr-1, R9-2), (R1-6, R2-1,R3-3, Pr-1, R9-3), (R1-6, R2-1, R3-3, Pr-2, R9-1), (R1-6, R2-1, R3-3,Pr-2, R9-2), (R1-6, R2-1, R3-3, Pr-2, R9-3), (R1-6, R2-1, R3-3, Pr-3,R9-1), (R1-6, R2-1, R3-3, Pr-3, R9-2), (R1-6, R2-1, R3-3, Pr-3, R9-3),(R1-6, R2-1, R3-3, Pr-4, R9-1), (R1-6, R2-1, R3-3, Pr-4, R9-2), (R1-6,R2-1, R3-3, Pr-4, R9-3), (R1-6, R2-1, R3-4, Pr-1, R9-1), (R1-6, R2-1,R3-4, Pr-1, R9-2), (R1-6, R2-1, R3-4, Pr-1, R9-3), (R1-6, R2-1, R3-4,Pr-2, R9-1), (R1-6, R2-1, R3-4, Pr-2, R9-2), (R1-6, R2-1, R3-4, Pr-2,R9-3), (R1-6, R2-1, R3-4, Pr-3, R9-1), (R1-6, R2-1, R3-4, Pr-3, R9-2),(R1-6, R2-1, R3-4, Pr-3, R9-3), (R1-6, R2-1, R3-4, Pr-4, R9-1), (R1-6,R2-1, R3-4, Pr-4, R9-2), (R1-6, R2-1, R3-4, Pr-4, R9-3), (R1-6, R2-1,R3-5, Pr-1, R9-1), (R1-6, R2-1, R3-5, Pr-1, R9-2), (R1-6, R2-1, R3-5,Pr-1, R9-3), (R1-6, R2-1, R3-5, Pr-2, R9-1), (R-6, R2-1, R3-5, Pr-2,R9-2), (R1-6, R2-1, R3-5, Pr-2, R9-3), (R1-6, R2-1, R3-5, Pr-3, R9-1),(R1-6, R2-1, R3-5, Pr-3, R9-2), (R1-6, R2-1, R3-5, Pr-3, R9-3), (R1-6,R2-1, R3-5, Pr-4, R9-1), (R1-6, R2-1, R3-5, Pr-4, R9-2), (R1-6, R2-1,R3-5, Pr-4, R9-3), (R1-6, R2-2, R3-1, Pr-1, R9-1), (R1-6, R2-2, R3-1,Pr-1, R9-2), (R1-6, R2-2, R3-1, Pr-1, R9-3), (R1-6, R2-2, R3-1, Pr-2,R9-1), (R1-6, R2-2, R3-1, Pr-2, R9-2), (R1-6, R2-2, R3-1, Pr-2, R9-3),(R1-6, R2-2, R3-1, Pr-3, R9-1), (R-6, R2-2, R3-1, Pr-3, R9-2), (R1-6,R2-2, R3-1, Pr-3, R9-3), (R1-6, R2-2, R3-1, Pr-4, R9-1), (R1-6, R2-2,R3-1, Pr-4, R9-2), (R1-6, R2-2, R3-1, Pr-4, R9-3), (R1-6, R2-2, R3-2,Pr-1, R9-1), (R1-6, R2-2, R3-2, Pr-1, R9-2), (R1-6, R2-2, R3-2, Pr-1,R9-3), (R1-6, R2-2, R3-2, Pr-2, R9-1), (R-6, R2-2, R3-2, Pr-2, R9-2),(R1-6, R2-2, R3-2, Pr-2, R9-3), (R1-6, R2-2, R3-2, Pr-3, R9-1), (R1-6,R2-2, R3-2, Pr-3, R9-2), (R1-6, R2-2, R3-2, Pr-3, R9-3), (R1-6, R2-2,R3-2, Pr-4, R9-1), (R-6, R2-2, R3-2, Pr-4, R9-2), (R1-6, R2-2, R3-2,Pr-4, R9-3), (R1-6, R2-2, R3-3, Pr-1, R9-1), (R1-6, R2-2, R3-3, Pr-1,R9-2), (R1-6, R2-2, R3-3, Pr-1, R9-3), (R1-6, R2-2, R3-3, Pr-2, R9-1),(R1-6, R2-2, R3-3, Pr-2, R9-2), (R1-6, R2-2, R3-3, Pr-2, R9-3), (R1-6,R2-2, R3-3, Pr-3, R9-1), (R1-6, R2-2, R3-3, Pr-3, R9-2), (R1-6, R2-2,R3-3, Pr-3, R9-3), (R1-6, R2-2, R3-3, Pr-4, R9-1), (R1-6, R2-2, R3-3,Pr-4, R9-2), (R1-6, R2-2, R3-3, Pr-4, R9-3), (R1-6, R2-2, R3-4, Pr-1,R9-1), (R1-6, R2-2, R3-4, Pr-1, R9-2), (R1-6, R2-2, R3-4, Pr-1, R9-3),(R1-6, R2-2, R3-4, Pr-2, R9-1), (R1-6, R2-2, R3-4, Pr-2, R9-2), (R1-6,R2-2, R3-4, Pr-2, R9-3), (R1-6, R2-2, R3-4, Pr-3, R9-1), (R1-6, R2-2,R3-4, Pr-3, R9-2), (R1-6, R2-2, R3-4, Pr-3, R9-3), (R1-6, R2-2, R3-4,Pr-4, R9-1), (R1-6, R2-2, R3-4, Pr-4, R9-2), (R1-6, R2-2, R3-4, Pr-4,R9-3), (R1-6, R2-2, R3-5, Pr-1, R9-1), (R1-6, R2-2, R3-5, Pr-1, R9-2),(R1-6, R2-2, R3-5, Pr-1, R9-3), (R1-6, R2-2, R3-5, Pr-2, R9-1), (R1-6,R2-2, R3-5, Pr-2, R9-2), (R1-6, R2-2, R3-5, Pr-2, R9-3), (R1-6, R2-2,R3-5, Pr-3, R9-1), (R-6, R2-2, R3-5, Pr-3, R9-2), (R1-6, R2-2, R3-5,Pr-3, R9-3), (R1-6, R2-2, R3-5, Pr-4, R9-1), (R1-6, R2-2, R3-5, Pr-4,R9-2), (R1-6, R2-2, R3-5, Pr-4, R9-3),

(R1-7, R2-1, R3-1, Pr-1, R9-1), (R1-7, R2-1, R3-1, Pr-1, R9-2), (R1-7,R2-1, R3-1, Pr-1, R9-3), (R1-7, R2-1, R3-1, Pr-2, R9-1), (R1-7, R2-1,R3-1, Pr-2, R9-2), (R1-7, R2-1, R3-1, Pr-2, R9-3), (R1-7, R2-1, R3-1,Pr-3, R9-1), (R1-7, R2-1, R3-1, Pr-3, R9- 2), (R1-7, R2-1, R3-1, Pr-3,R9-3), (R1-7, R2-1, R3-1, Pr-4, R9-1), (R1-7, R2-1, R3-1, Pr-4, R9-2),(R1-7, R2-1, R3-1, Pr-4, R9-3), (R-7, R2-1, R3-2, Pr-1, R9-1), (R1-7,R2-1, R3-2, Pr-1, R9-2), (R1-7, R2-1, R3-2, Pr-1, R9-3), (R1-7, R2-1,R3-2, Pr-2, R9-1), (R1-7, R2-1, R3-2, Pr-2, R9-2), (R1-7, R2-1, R3,Pr-2, R9-3), (R-7, R2-1, R3-2, Pr-3, R9-1), (R1-7, R2-1, R3-2, Pr-3,R9-2), (R1-7, R2-1, R3-2, Pr-3, R9-3), (R1-7, R2-1, R3-2, Pr-4, R9-1),(R1-7, R2-1, R3-2, Pr-4, R9-2), (R1-7, R2-1, R3-2, Pr-4, R9-3), (R1-7,R2-1, R3-3, Pr-1, R9-1), (R1-7, R2-1, R3-3, Pr-1, R9-2), (R1-7, R2-1,R3-3, Pr-1, R9-3), (R1-7, R2-1, R3-3, Pr-2, R9-1), (R1-7, R2-1, R3-3,Pr-2, R9-2), (R1-7, R2-1, R3-3, Pr-2, R9-3), (R1-7, R2-1, R3-3, Pr-3,R9-1), (R1-7, R2-1, R3-3, Pr-3, R9-2), (R1-7, R2-1, R3-3, Pr-3, R9-3),(R1-7, R2-1, R3-3, Pr-4, R9-1), (R1-7, R2-1, R3-3, Pr-4, R9-2), (R1-7,R2-1, R3-3, Pr-4, R9-3), (R1-7, R2-1, R3-4, Pr-1, R9-1), (R1-7, R2-1,R3-4, Pr-1, R9-2), (R1-7, R2-1, R3-4, Pr-1, R9-3), (R1-7, R2-1, R3-4,Pr-2, R9-1), (R1-7, R2-1, R3-4, Pr-2, R9-2), (R1-7, R2-1, R3-4, Pr-2,R9-3), (R1-7, R2-1, R3-4, Pr-3, R9-1), (R1-7, R2-1, R3-4, Pr-3, R9-2),(R1-7, R2-1, R3-4, Pr-3, R9-3), (R1-7, R2-1, R3-4, Pr-4, R9-1), (R1-7,R2-1, R3-4, Pr-4, R9-2), (R1-7, R2-1, R3-4, Pr-4, R9-3), (R1-7, R2-1,R3-5, Pr-1, R9-1), (R1-7, R2-1, R3-5, Pr-1, R9-2), (R1-7, R2-1, R3-5,Pr-1, R9-3), (R1-7, R2-1, R3-5, Pr-2, R9-1), (R1-7, R2-1, R3-5, Pr-2,R9-2), (R1-7, R2-1, R3-5, Pr-2, R9-3), (R1-7, R2-1, R3-5, Pr-3, R9-1),(R1-7, R2-1, R3-5, Pr-3, R9-2), (R1-7, R2-1, R3-5, Pr-3, R9-3), (R1-7,R2-1, R3-5, Pr-4, R9-1), (R1-7, R2-1, R3-5, Pr-4, R9-2), (R1-7, R2-1,R3-5, Pr-4, R9-3), (R1-7, R2-2, R3-1, Pr-1, R9-1), (R1-7, R2-2, R3-1,Pr-1, R9-2), (R1-7, R2-2, R3-1, Pr-1, R9-3), (R1-7, R2-2, R3-1, Pr-2,R9-1), (R1-7, R2-2, R3-1, Pr-2, R9-2), (R1-7, R2-2, R3-1, Pr-2, R9-3),(R1-7, R2-2, R3-1, Pr-3, R9-1), (R1-7, R2-2, R3-1, Pr-3, R9-2), (R1-7,R2-2, R3-1, Pr-3, R9-3), (R1-7, R2-2, R3-1, Pr-4, R9-1), (R1-7, R2-2,R3-1, Pr-4, R9-2), (R1-7, R2-2, R3-1, Pr-4, R9-3), (R1-7, R2-2, R3-2,Pr-1, R9-1), (R1-7, R2-2, R3-2, Pr-1, R9-2), (R1-7, R2-2, R3-2, Pr-1,R9-3), (R1-7, R2-2, R3-2, Pr-2, R9-1), (R1-7, R2-2, R3-2, Pr-2, R9-2),(R1-7, R2-2, R3-2, Pr-2, R9-3), (R1-7, R2-2, R3-2, Pr-3, R9-1), (R1-7,R2-2, R3-2, Pr-3, R9-2), (R1-7, R2-2, R3-2, Pr-3, R9-3), (R1-7, R2-2,R3-2, Pr-4, R9-1), (R1-7, R2-2, R3-2, Pr-4, R9-2), (R1-7, R2-2, R3-2,Pr-4, R9-3), (R1-7, R2-2, R3-3, Pr-1, R9-1), (R1-7, R2-2, R3-3, Pr-1,R9-2), (R1-7, R2-2, R3-3, Pr-1, R9-3), (R1-7, R2-2, R3-3, Pr-2, R9-1),(R1-7, R2-2, R3-3, Pr-2, R9-2), (R1-7, R2-2, R3-3, Pr-2, R9-3), (R1-7,R2-2, R3-3, Pr-3, R9-1), (R1-7, R2-2, R3-3, Pr-3, R9-2), (R1-7, R2-2,R3-3, Pr-3, R9-3), (R1-7, R2-2, R3-3, Pr-4, R9-1), (R1-7, R2-2, R3-3,Pr-4, R9-2), (R1-7, R2-2, R3-3, Pr-4, R9-3), (R1-7, R2-2, R3-4, Pr-1,R9-1), (R1-7, R2-2, R3-4, Pr-1, R9-2), (R1-7, R2-2, R3-4, Pr-1, R9-3),(R1-7, R2-2, R3-4, Pr-2, R9-1), (R1-7, R2-2, R3-4, Pr-2, R9-2), (R1-7,R2-2, R3-4, Pr-2, R9-3), (R1-7, R2-2, R3-4, Pr-3, R9-1), (R1-7, R2-2,R3-4, Pr-3, R9-2), (R1-7, R2-2, R3-4, Pr-3, R9-3), (R1-7, R2-2, R3-4,Pr-4, R9-1), (R1-7, R2-2, R3-4, Pr-4, R9-2), (R1-7, R2-2, R3-4, Pr-4,R9-3), (R1-7, R2-2, R3-5, Pr-1, R9-1), (R1-7, R2-2, R3-5, Pr-1, R9-2),(R1-7, R2-2, R3-5, Pr-1, R9-3), (R1-7, R2-2, R3-5, Pr-2, R9-1), (R1-7,R2-2, R3-5, Pr-2, R9-2), (R1-7, R2-2, R3-5, Pr-2, R9-3), (R1-7, R2-2,R3-5, Pr-3, R9-1), (R1-7, R2-2, R3-5, Pr-3, R9-2), (R1-7, R2-2, R3-5,Pr-3, R9-3), (R1-7, R2-2, R3-5, Pr-4, R9-1), (R1-7, R2-2, R3-5, Pr-4,R9-2), (R1-7, R2-2, R3-5, Pr-4, R9-3),

(R1-8, R2-1, R3-1, Pr-1, R9-1), (R1-8, R2-1, R3-1, Pr-1, R9-2), (R1-8,R2-1, R3-1, Pr-1, R9-3), (R1-8, R2-1, R3-1, Pr-2, R9-1), (R1-8, R2-1,R3-1, Pr-2, R9-2), (R1-8, R2-1, R3-1, Pr-2, R9-3), (R1-8, R2-1, R3-1,Pr-3, R9-1), (R1-8, R2-1, R3-1, Pr-3, R9- 2), (R1-8, R2-1, R3-1, Pr-3,R9-3), (R1-8, R2-1, R3-1, Pr-4, R9-1), (R1-8, R2-1, R3-1, Pr-4, R9-2),(R-8, R2-1, R3-1, Pr-4, R9-3), (R1-8, R2-1, R3-2, Pr-1, R9-1), (R1-8,R2-1, R3-2, Pr-1, R9-2), (R1-8, R2-1, R3-2, Pr-1, R9-3), (R1-8, R2-1,R3-2, Pr-2, R9-1), (R1-8, R2-1, R3-2, Pr-2, R9-2), (R1-8, R2-1, R3-2,Pr-2, R9-3), (R1-8, R2-1, R3-2, Pr-3, R9-1), (R1-8, R2-1, R3-2, Pr-3,R9-2), (R1-8, R2-1, R3-2, Pr-3, R9-3), (R1-8, R2-1, R3-2, Pr-4, R9-1),(R1-8, R2-1, R3-2, Pr-4, R9-2), (R1-8, R2-1, R3-2, Pr-4, R9-3), (R1-8,R2-1, R3-3, Pr-1, R9-1), (R1-8, R2-1, R3-3, Pr-1, R9-2), (R1-8, R2-1,R3-3, Pr-1, R9-3), (R1-8, R2-1, R3-3, Pr-2, R9-1), (R1-8, R2-1, R3-3,Pr-2, R9-2), (R1-8, R2-1, R3-3, Pr-2, R9-3), (R1-8, R2-1, R3-3, Pr-3,R9-1), (R1-8, R2-1, R3-3, Pr-3, R9-2), (R1-8, R2-1, R3-3, Pr-3, R9-3),(R1-8, R2-1, R3-3, Pr-4, R9-1), (R1-8, R2-1, R3-3, Pr-4, R9-2), (R1-8,R2-1, R3-3, Pr-4, R9-3), (R1-8, R2-1, R3-4, Pr-1, R9-1), (R1-8, R2-1,R3-4, Pr-1, R9-2), (R1-8, R2-1, R3-4, Pr-1, R9-3), (R1-8, R2-1, R3-4,Pr-2, R9-1), (R1-8, R2-1, R3-4, Pr-2, R9-2), (R1-8, R2-1, R3-4, Pr-2,R9-3), (R1-8, R2-1, R3-4, Pr-3, R9-1), (R1-8, R2-1, R3-4, Pr-3, R9-2),(R1-8, R2-1, R3-4, Pr-3, R9-3), (R1-8, R2-1, R3-4, Pr-4, R9-1), (R1-8,R2-1, R3-4, Pr-4, R9-2), (R1-8, R2-1, R3-4, Pr-4, R9-3), (R1-8, R2-1,R3-5, Pr-1, R9-1), (R1-8, R2-1, R3-5, Pr-1, R9-2), (R1-8, R2-1, R3-5,Pr-1, R9-3), (R1-8, R2-1, R3-5, Pr-2, R9-1), (R1-8, R2-1, R3-5, Pr-2,R9-2), (R1-8, R2-1, R3-5, Pr-2, R9-3), (R1-8, R2-1, R3-5, Pr-3, R9-1),(R1-8, R2-1, R3-5, Pr-3, R9-2), (R1-8, R2-1, R3-5, Pr-3, R9-3), (R1-8,R2-1, R3-5, Pr-4, R9-1), (R1-8, R2-1, R3-5, Pr-4, R9-2), (R1-8, R2-1,R3-5, Pr-4, R9-3), (R1-8, R2-2, R3-1, Pr-1, R9-1), (R1-8, R2-2, R3-1,Pr-1, R9-2), (R1-8, R2-2, R3-1, Pr-1, R9-3), (R1-8, R2-2, R3-1, Pr-2,R9-1), (R1-8, R2-2, R3-1, Pr-2, R9-2), (R1-8, R2-2, R3-1, Pr-2, R9-3),(R1-8, R2-2, R3-1, Pr-3, R9-1), (R1-8, R2-2, R3-1, Pr-3, R9-2), (R1-8,R2-2, R3-1, Pr-3, R9-3), (R1-8, R2-2, R3-1, Pr-4, R9-1), (R1-8, R2-2,R3-1, Pr-4, R9-2), (R1-8, R2-2, R3-1, Pr-4, R9-3), (R1-8, R2-2, R3-2,Pr-1, R9-1), (R1-8, R2-2, R3-2, Pr-1, R9-2), (R1-8, R2-2, R3-2, Pr-1,R9-3), (R1-8, R2-2, R3-2, Pr-2, R9-1), (R1-8, R2-2, R3-2, Pr-2, R9-2),(R1-8, R2-2, R3-2, Pr-2, R9-3), (R1-8, R2-2, R3-2, Pr-3, R9-1), (R1-8,R2-2, R3-2, Pr-3, R9-2), (R1-8, R2-2, R3-2, Pr-3, R9-3), (R1-8, R2-2,R3-2, Pr-4, R9-1), (R1-8, R2-2, R3-2, Pr-4, R9-2), (R1-8, R2-2, R3-2,Pr-4, R9-3), (R1-8, R2-2, R3-3, Pr-1, R9-1), (R1-8, R2-2, R3-3, Pr-1,R9-2), (R1-8, R2-2, R3-3, Pr-1, R9-3), (R1-8, R2-2, R3-3, Pr-2, R9-1),(R1-8, R2-2, R3-3, Pr-2, R9-2), (R1-8, R2-2, R3-3, Pr-2, R9-3), (R1-8,R2-2, R3-3, Pr-3, R9-1), (R1-8, R2-2, R3-3, Pr-3, R9-2), (R1-8, R2-2,R3-3, Pr-3, R9-3), (R1-8, R2-2, R3-3, Pr-4, R9-1), (R1-8, R2-2, R3-3,Pr-4, R9-2), (R1-8, R2-2, R3-3, Pr-4, R9-3), (R1-8, R2-2, R3-4, Pr-1,R9-1), (R1-8, R2-2, R3-4, Pr-1, R9-2), (R1-8, R2-2, R3-4, Pr-1, R9-3),(R1-8, R2-2, R3-4, Pr-2, R9-1), (R1-8, R2-2, R3-4, Pr-2, R9-2), (R1-8,R2-2, R3-4, Pr-2, R9-3), (R1-8, R2-2, R3-4, Pr-3, R9-1), (R1-8, R2-2,R3-4, Pr-3, R9-2), (R1-8, R2-2, R3-4, Pr-3, R9-3), (R1-8, R2-2, R3-4,Pr-4, R9-1), (R1-8, R2-2, R3-4, Pr-4, R9-2), (R1-8, R2-2, R3-4, Pr-4,R9-3), (R1-8, R2-2, R3-5, Pr-1, R9-1), (R1-8, R2-2, R3-5, Pr-1, R9-2),(R1-8, R2-2, R3-5, Pr-1, R9-3), (R1-8, R2-2, R3-5, Pr-2, R9-1), (R1-8,R2-2, R3-5, Pr-2, R9-2), (R1-8, R2-2, R3-5, Pr-2, R9-3), (R1-8, R2-2,R3-5, Pr-3, R9-1), (R1-8, R2-2, R3-5, Pr-3, R9-2), (R1-8, R2-2, R3-5,Pr-3, R9-3), (R1-8, R2-2, R3-5, Pr-4, R9-1), (R1-8, R2-2, R3-5, Pr-4,R9-2), (R1-8, R2-2, R3-5, Pr-4, R9-3).

(Method for Producing Compound of the Present Invention)

A general method for producing the compound of the present inventionwill be exemplified below. And, as extraction and purification,treatment which is performed in a normal experiment of organic chemistrymay be conducted.

Synthesis of the compound of the present invention can be carried outreferring to the procedures known in the art.

As a raw material compound, commercially available compounds, compoundsdescribed in the present description, compounds described in thereferences cited in the present description, and other known compoundscan be utilized.

Among the compounds of the present invention, there are compounds inwhich a tautomer can be present, and the present invention includes allpossible isomers and a mixture thereof, including them.

When one wants to obtain a salt of the compound of the presentinvention, in the case where the compound of the present invention isobtained in a form of a salt, it may be purified as it is and, in thecase where the compound of the present invention is obtained in a freeform, a salt may be formed by a normal method by dissolving orsuspending the compound in a suitable organic solvent, and adding anacid or a base. In addition, the compound of the present invention and apharmaceutically acceptable salt thereof are present in a form ofadducts with water or various solvents (hydrate or solvate) in somecases, and these adducts are included in the present invention.

In a general synthesis method as well as Reference examples, Examples,and Intermediate Synthesis Examples, the meaning of each abbreviation isas follows.

DMF: N,N-dimethylformamide DMA: N,N-dimethylacetamide, NMP:N-methylpyrrolidone

DM: dimethylimidazolidinoneTHF: tetrahydrofuranMs: methanesulfonylTs: paratoluenesulfonylBoc: tert-butoxycarbonylDIBALH: diisobutylaluminum hydrideWSC or EDCI: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimideHOBt: 1-hydroxybenzotriazoleHATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

NBS: N-bromosuccinimide NCS: N-chlorosuccinimide

TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl radicalPDC: pyridinium dichloromateDEAD: diethyl azodicarboxylateDIAD: diisopropyl azodicarboxylateDMAP: 4-dimethylaminopyridinemCPBA: m-chloroperbenzoic acidDBU: 1,8-diazabicyclo[5.4.0]-7-undeceneDIPEA: diisopropylethylamineTBAF: tetrabutylammonium fluorideIBX: 2-iodoxybenzoic acidDMSO: dimethyl sulfoxideNaHMDS: sodium hexamethyldisilazideTFA: trifluoroacetic acidAc: acetylTBS: tert-butyldimethylsilylPEPPSITM-IPr:(1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II)dichlorideBEMP:2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine

Synthesis of Compound aj of Reference Example (See: Reference Example 1)

(wherein R is carboxy protective group, P¹ is hydroxyl protective group,R₂, R³, R⁸, R⁹, R¹⁰ and R¹¹ are same as R^(2a), R^(3a), R^(8a), R^(9a),R^(10a) and R^(11a) in item 1, respectively, R and P¹ may be a groupwhich can be protected and/or deprotected by the method described inProtective Groups in Organic Synthesis, Theodora W Green (John Wiley &Sons) etc. and, for example, R is lower alkyl etc., and P¹ is arylalkyletc.)

First Step

A compound ab can be obtained by reacting a compound aa which iscommercially available or can be prepared by the known method at −20° C.to 30° C., preferably 0° C. to 20° C. for 0.1 hours to 24 hours,preferably 0.5 hours to 12 hours in a solvent such as dichloromethane,toluene, THF etc. or a mixed solvent thereof, by adding dropwisetertiary amine such as pyridine, trimethylamine, N-methylmorpholine,4-dimethylaminopyridine etc. and benzyloxyacetyl chloride.

Second Step

A compound ac can be obtained by adding an organometallic base such aslithium hexamethyldisilazane, lithium diisopropylamide, butyllithium,tert-butyllithium etc. to the compound ab in a solvent such as ether,dichloromethane, THF etc. or a mixed solvent thereof, in the presence ofcinnamoyl chloride, and performing a reaction at −80° C. to 0° C.,preferably −80° C. to −40° C. for 1 minute to 2 hours, preferably 10minutes to 1 hour.

Third Step

A compound ad can be obtained by adding a catalytic amount of anoxidizing agent such as ruthenium chloride and sodium periodate, TEMPO,manganese dioxide, as well as PDC etc. to the compound ac in a solventsuch as ether, dichloromethane, THF, acetonitrile etc. or a mixedsolvent thereof, and performing a reaction at −40° C. to 80° C.,preferably 0° C. to 40° C. for 0.1 hours to 24 hours, preferably 0.2hours to 3 hours.

Fourth Step

Concentrated sulfuric acid and an aqueous solution of amidosululic acidare added to the compound ad at 0° C. to 60° C., preferably 10° C. to40° C. in the presence of a solvent such as ether, dichloromethane, THF,acetonitrile, acetone, water etc. or in a mixed solvent thereof. Anaqueous sodium chlorite solution is added dropwise thereto at the sametemperature to perform a reaction for 1 minute to 3 hours, preferably 5minutes to 1 hour, thereby, a compound ae can be obtained.

Fifth Step

A compound af can be obtained by adding a compound R³—NH₂ having asubstituent corresponding to an objective compound to the compound ae ina solvent such as DMF, THF, dichloromethane, acetonitrile etc. in thepresence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5,-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl, HATUetc., and performing a reaction at −20° C. to 60° C., preferably −10° C.to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours.

Sixth Step

A compound ah can be obtained by adding a compound ag to the compound afin the presence of a solvent such as toluene, xylene, THF, dioxane etc.or in a mixed solvent thereof, and performing a reaction for 0.1 hoursto 12 hours, preferably 0.2 hours to 6 hours under the heat-refluxingcondition.

Seventh Step

A compound ai can be obtained by adding triphenylphosphine and acondensation agent such as DEAD, DIAD etc. to the compound ah in thepresence of a solvent such as THF, dioxane, ethyl acetate, acetonitrileetc. or in a mixed solvent thereof, and performing a reaction at 0° C.to 60° C., preferably 10° C. to 40° C. for 0.1 hours to 12 hours,preferably 0.2 hours to 6 hours.

Eighth Step

By subjecting the compound ai to the known general deprotecting reactionof a carboxyl protective group and a hydroxyl protective group, acompound aj can be obtained.

Synthesis of Compound bk of Reference Example (See: Reference Example12)

(wherein P² is amino protective group, P² may be a group which can beprotected and/or deprotected by the method described in ProtectiveGroups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.and, for example, P² is arylalkyloxycarbonyl, lower alkyloxycarbonyl,etc. Other each symbol is same as above.)

First Step

A compound bb can be obtained by adding a base such as potassiumcarbonate, sodium carbonate, cesium carbonate etc. and a compound P²-L(wherein L is a leaving group such as halogen, OMs etc.) having asubstituent corresponding to an objective compound to a compound ba inthe presence of a solvent such as DMF, THF, dioxane, acetonitrile etc.or in a mixed solvent thereof, and performing a reaction at −20° C. to80° C., preferably 0° C. to 50° C. for 0.1 hours to 6 hours, preferably0.2 hours to 6 hours.

Second Step

A compound be can be obtained by adding triphenylphosphine andphthalimide to the compound bb in the presence of a solvent such as DMF,THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, adding adehydration-condensation reagent such as DIAD, DEAD etc., and performinga reaction at −10° C. to 60° C., preferably 0° C. to 50° C. for 0.1hours to 24 hours, preferably 0.2 hours to 12 hours.

Third Step

A compound bd can be obtained by adding hydrazine hydrate ormethylhydrazine to the compound be in the presence of a solvent such asmethanol, THF, dioxane, acetonitrile, etc. or in a mixed solventthereof, and performing a reaction at −10° C. to 80° C., preferably 10°C. to 60° C. for 0.5 hours to 24 hours, preferably 1 to 12 hours.

Fourth Step

A compound be can be obtained by adding Boc₂O to the compound bd in thepresence of a solvent such as THF, dioxane, acetonitrile etc. or in amixed solvent thereof, and performing a reaction at −10° C. to 80° C.,preferably 10° C. to 60° C. for 0.5 hours to 24 hours, preferably 1 to12 hours.

Fifth Step

A compound bf can be obtained by subjecting the compound be to the knowngeneral deprotecting reaction of an amino protective group.

Sixth Step

A compound bh can be obtained by adding a compound bg to the compound bfin the presence of a solvent such as toluene, THF, dioxane, acetonitrileetc. or in a mixed solvent thereof, and performing a reaction at 20° C.to 110° C., preferably 40° C. to under heat-refluxing for 0.5 hours to24 hours, preferably 1 hour to 12 hours.

Seventh Step

HCl-ethyl acetate, HCl-dioxane, formic acid etc. is added to thecompound bh, and they are reacted at 0° C. to 40° C., preferably 0° C.to 20° C. for 0.5 hours to 12 hours, preferably 1 hour to 6 hours. Afterthe solvent is distilled off under reduced pressure, an aqueoussaturated sodium bicarbonate solution is added, and the mixture isstirred, thereby, a compound bi can be obtained.

Eighth Step

A compound bj can be obtained by adding a base such as potassiumcarbonate, sodium carbonate, lithium carbonate, cesium carbonate etc.and a compound R³-L (L is a leaving group such as halogen, OMs etc.) tothe compound bi in the presence of a solvent such as DMF, THF, DMA, NMPetc. or in a mixed solvent thereof, and performing a reaction at 0° C.to 60° C., preferably 10° C. to 30° C. for 0.5 hours to 12 hours,preferably 1 hour to 6 hours.

Ninth Step

A compound bk can be obtained by subjecting the compound bj to the knowngeneral deprotecting reaction of a carboxyl protective group and ahydroxyl protective group.

Synthesis of Compound cd of Reference Example (See: Reference Examples28 and 43)

(wherein each symbol is same as above)

First Step

A compound cb can be obtained by adding tertiary amine such astriethylamine, DMAP, morpholine etc. or a base such as sodium carbonate,sodium bicarbonate etc. to a compound ca in the presence of a solventsuch as THF, dioxane, acetonitrile, water etc. or in a mixed solventthereof, adding Boc₂O, and performing a reaction at −10° C. to 80° C.,preferably 10° C. to 60° C. for 0.5 hours to 24 hours, preferably 1 to12 hours.

Second Step

A compound cc can be obtained by adding triphenylphosphine andphthalimide to the compound cb in the presence of a solvent such as DMF,THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, adding adehydration-condensation reagent such as DIAD, DEAD etc., and performinga reaction at −10° C. to 60° C., preferably 0° C. to 50° C. for 0.1hours to 24 hours, preferably 0.2 hours to 12 hours.

Third Step

A compound cd can be obtained by adding hydrazine hydrate to thecompound cc in the presence of a solvent such as methanol, THF, dioxane,acetonitrile etc. or in a mixed solvent thereof, and performing areaction at −10° C. to 80° C., preferably 10° C. to 60° C. for 0.5 hoursto 24 hours, preferably 1 to 12 hours.

Synthesis of Compound Dg of Reference Example (See: Reference Examples36, 41, and 46)

dg

(wherein B¹ and B² are same as those of item 1, and other each symbol issame as above).

First Step

A compound db can be obtained by subjecting the compound da obtained bythe same method as the synthesis method of bi to the known generalcarboxyl deprotecting reaction.

Second Step

A decarbonized compound dc can be obtained by reacting the compound dbfor 1 minute to 2 hours under microwave irradiation in a solvent such asdiphenyl ether etc. And, a decarbonized compound d can be obtained byadding copper in a quinoline solvent, and performing a reaction at 180°C. for 2 to 48 hours.

Third Step

A compound bd can be obtained by adding a base such as potassiumcarbonate, sodium carbonate, lithium carbonate, cesium carbonate etc.and a compound R³-L (L is a leaving group such as halogen, OMs etc.) tothe compound da obtained by the method described in Reference example 12in the presence of a solvent such as DMF, THF, DMA, NMP etc. or in amixed solvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 30° C. for 0.5 hours to 12 hours, preferably 1 hourto 6 hours.

Fourth Step

A compound de can be obtained by the same method as that of the firststep.

Fifth Step

A compound df can be obtained by the same method as that of the secondstep.

Sixth Step

A compound df can be obtained by the same method as that of the thirdstep.

Seventh Step

A compound dg can be obtained by subjecting the compound df to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound Ec of Reference Example (See: Reference Example48)

(wherein each symbol is same as above)

First Step

A base such as triethylamine, N-methylmorpholine, diisopropylethylamineetc. and ethyl chloroformate are added to a compound ea in the presenceof a solvent such as THF, dioxane, dichloromethane, toluene etc. or in amixed solvent thereof. A reducing agent having a low reducing power suchas sodium borohydride etc. is added thereto, and a reaction is performedat −20° C. to 60° C., preferably −10° C. to 20° C. for 0.2 hours to 12hours, preferably 0.5 hours to 6 hours, thereby, a compound eb can beobtained.

Second Step

A compound ec can be obtained by subjecting the compound eb to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound fh of Reference Example (See: Reference Example50)

(wherein R¹ is a group corresponding to R^(1a) in item 1, and other eachsymbol is same as above)

First Step

A compound fb and triphenylphosphine are added to a compound fa in thepresence of a solvent such as THF, dichloromethane, dioxane,acetonitrile etc. or in a mixed solvent thereof. DIAD is added thereto,and a reaction is performed at 0° C. to 60° C., preferably 10° C. to 30°C. for 0.5 hours to 12 hours, preferably 1 hour to 12 hours, thereby, acompound fc can be obtained.

Second Step

A compound fd can be obtained by adding a base such as potassiumcarbonate, sodium carbonate, lithium carbonate, cesium carbonate etc.and thiol such as benzenethiol etc. to the compound fc in the presenceof a solvent such as THF, dioxane, acetonitrile etc. or in a mixedsolvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 30° C. for 0.5 hours to 12 hours, preferably 1 hourto 12 hours.

Third Step

A compound ff can be obtained by adding a compound fe having asubstituent corresponding to an objective compound to the compound fd ina solvent such as DMF, THF, dichloromethane, acetonitrile etc. in thepresence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl etc.,and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40°C. for 1 hour to 48 hours, preferably 2 hours to 24 hours.

Fourth Step

A compound fd can be obtained by subjecting the compound ff to the knowngeneral deprotecting reaction concerning a P² group on an amino group,subsequently, adding a base such as an aqueous sodium carbonatesolution, an aqueous potassium carbonate solution etc. in a solvent suchas water, ethanol, methanol, acetonitrile etc. or in a mixed solventthereof, and performing a reaction at 20° C. to 80° C., preferably 20°C. to 70° C. for 0.5 hours to 24 hours, preferably 1 hour to 6 hours.

Fifth Step

A compound fh can be obtained by subjecting the compound fg to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound ga of Reference Example (See: Reference Example51)

(wherein each symbol is same as above)

First Step

A compound ga can be obtained by subjecting a compound dd to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound hh of Reference example (see: Reference Example52)

(wherein each symbol is same as above)

First Step

A compound hb can be obtained by adding O,N-dimethylhydroxylaminehydrochloride to a compound ha in a solvent such as DMF, THF,dichloromethane, acetonitrile etc. in the presence of adehydration-condensation agent such as dicyclohexylcarbodiimide,carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl, HATUetc., adding a tertiary base such as triethylamine,diisopropylethylamine, N-methylmorpholine etc., and performing areaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 1 hour to24 hours, preferably 1 hour to 12 hours.

Second Step

A compound he can be obtained by adding a Grignard reagent (R—MgBr) tothe compound hb at −80° C. to −40° C. in the presence of a solvent suchas THF, ether, dichloromethane, dioxane etc. or in a mixed solventthereof, and performing a reaction at −80° C. to 0° C., preferably −60°C. to −20° C. for 0.5 hours to 24 hours, preferably 0.5 hours to 6hours.

Third Step

A compound hd can be obtained by adding mCPBA to the compound he in thepresence of a solvent such as chloroform and dichloromethane, andperforming a reaction at −20° C. to 30° C., preferably 10° C. to 30° C.for 0.1 hours to 12 hours, preferably 0.5 hours to 6 hours.

Fourth Step

A compound he can be obtained by adding an aqueous sodium hydroxidesolution to the compound hd in the presence of a solvent such as ethanoletc., and performing a reaction at 0° C. to 120° C., preferably 30° C.to 90° C. for 1 minute to 10 hours, preferably 30 minutes to 120minutes.

Fifth Step

A compound hf can be obtained by subjecting the compound he to the knowngeneral hydroxyl group deprotecting reaction.

Sixth Step

A compound hg can be obtained by adding a compound R—Br etc.corresponding to an objective compound to a compound he in the presenceof a solvent such as chloroform, dichloromethane, THF, toluene etc. orin a mixed solvent thereof, adding a metal base such as sodium hydride,sodium methylate, n-butyllithium etc., and performing a reaction at −20°C. to 120° C., preferably 0° C. to 30° C. for 0.5 hours to 12 hours,preferably 1 hour to 6 hours.

Seventh Step

A compound hh can be obtained by subjecting the compound hg to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound ic of Reference Example (See: Reference Example53)

(wherein each symbol is same as above)

First Step

Tertiary amine such as triethylamine, diisopropylethylamine,N-methylmorpholine etc., and a chlorinating reagent such as ethylchlorocarbonate, and ethyl chloroformate are added to a compound ia inthe presence of a solvent such as DMF, DMA, NMP, THF etc. or in a mixedsolvent thereof, and the mixture is stirred at 0° C. to 30° C. for 0.1hours to 1 hour. A compound R—SO₂—NH₂ (e.g.: methanesulfonylamide)corresponding to an objective substance and DMAP are added thereto, anda reaction is performed at 40° C. to 100° C., preferably 40° C. to 80°C. for 0.5 hours to 12 hours, preferably 1 hour to 6 hours, thereby, acompound ib can be obtained.

Second Step

A compound ic can be obtained by subjecting the compound ib to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound je of Reference Example (See: Reference Example54)

(wherein each symbol is same as above)

First Step

Tertiary amine such as triethylamine, N-methylmorpholine,diisopropylethylamine etc. and ethyl chloroformate or ethylchlorocarbonate are added to a compound ja in the presence of a solventsuch as THF, dioxane, dichloromethane, toluene, DMF etc. or in a mixedsolvent thereof. A reducing agent having low reactivity such as sodiumborohydride etc. is added thereto, and a reaction is performed at −20°C. to 40° C., preferably −10° C. to 20° C. for 0.2 hours to 12 hours,preferably 0.5 hours to 6 hours to obtain an alcohol intermediate. Thisintermediate is dissolved in dichloromethane, chloroform, etc., anoxidizing agent such as TEMPO, manganese dioxide, PDC etc. is added, anda reaction is performed at −40° C. to 30° C., preferably 0° C. to 30° C.for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours, thereby, acompound jb can be obtained.

Second Step

A compound jc can be obtained by adding 28% aqueous ammonia and iodineto the compound jb in the presence of a solvent such as THF, dioxane,dichloromethane etc., and performing a reaction at 0° C. to 40° C.,preferably 10° C. to 30° C. for 0.5 hours to 24 hours, preferably 1 hourto 6 hours.

Third Step

A compound jd can be obtained by adding sodium azide, and tertiary aminesuch as triethylamine, diisopropylethylamine, N-methylmorpholine etc. tothe compound jc in the presence of a solvent such as toluene, xylene,THF, dioxane etc. or in a mixed solvent thereof, and performing areaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.5 hoursto 24 hours, preferably 1 hour to 12 hours.

Fourth Step

A compound je can be obtained by subjecting the compound jd to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compounds kd and kf of Reference Example (See: ReferenceExample 56 and Derivative Thereof)

(wherein R^(m) is lower alkyl, R is a substituent corresponding to anobjective compound, W is —C(═O)— or —SO₂—, and other each symbol is sameas above)

First Step

Tertiary amine such as triethylamine, N-methylmorpholine,diisopropylethylamine etc. and ethyl chloroformate or ethylchlorocarbonate are added to a compound ka in the presence of a solventsuch as THF, dioxane, dichloromethane, toluene, DMF etc. or in a mixedsolvent thereof. Sodium azide is added thereto to perform a reaction at0° C. to 40° C., preferably 10° C. to 30° C. for 0.5 hours to 24 hours,preferably 1 hour to 12 hours. Thereafter, an alcohol (R^(m)—OH) isadded, and a reaction is performed at 20° C. to 60° C., preferably 20°C. to 50° C. for 0.5 hours to 24 hours, preferably 1 hour to 12 hours,thereby, a compound kb can be obtained.

Second Step

A compound kc can be obtained by adding a base such as an aqueous sodiumhydroxide solution, an aqueous potassium hydroxide solution etc. to thecompound kb in a solvent such as ethanol, methanol, water etc. or in amixed solvent thereof, and performing a reaction at 20° C. to 80° C.,preferably 40° C. to 60° C. for 0.5 hours to 24 hours, preferably 1 hourto 12 hours.

Third Step

A compound kd can be obtained by subjecting the compound kc to the knowngeneral hydroxyl group deprotecting reaction.

Fourth Step

A compound ke can be obtained by adding acid chloride (R—CO—Cl) orsulfonyl chloride (R—SO₂—Cl) corresponding to an objective substance toa compound kc in a solvent such as THF, dioxane, toluene,dichloromethane etc., adding tertiary amine such as pyridine,triethylamine, N-methylmorpholine etc. as necessary, and performing areaction at −20° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hoursto 12 hours, preferably 0.2 hours to 6 hours.

Fifth Step

A compound kf can be obtained by subjecting the compound ke to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound lc of Reference Example (See: Reference Example60)

(wherein R is a substituent corresponding to an objective compound, andother each symbol is same as above)

First Step

Sodium hydride is added to a compound 1a in a solvent such as THF,dichloromethane, DMF etc. R-L (L is a leaving group such as halogen, OMsetc.) corresponding to an objective substance is added thereto, and areaction is performed at −20° C. to 40° C., preferably 0° C. to 30° C.for 0.1 hours to 12 hours, preferably 0.2 hours to 6 hours, thereby, acompound 1b can be obtained.

Alternatively, a compound 1b can be obtained by adding formaldehyde to acompound 1a in a solvent of formic acid, and performing a reaction at70° C. to 110° C. for 0.5 hours to 24 hours, preferably 1 hour to 12hours.

Second Step

A compound 1c can be obtained by subjecting the compound 1b to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound md of Reference Example (See: Reference Example61)

(wherein R is a substituent corresponding to an objective compound, andother each symbol is same as above)

First Step

An amino-protected body mb can be obtained by adding Boc₂O etc. to acompound ma in a solvent such as THF, dioxane, acetonitrile, water etc.or in a mixed solvent thereof, and subjecting this to an amineprotecting reaction.

Second Step

Sodium hydride is added to a compound mb in a solvent such as THF,dichloromethane, DMF etc. R-L (L is a leaving group such as halogen, OMsetc.) corresponding to an objective substance is added thereto, and areaction is performed at −20° C. to 40° C., preferably 0° C. to 30° C.for 0.1 hours to 12 hours, preferably 0.2 hours to 6 hours, thereby, acompound me can be obtained.

Third Step

A compound md can be obtained by subjecting the compound me to the knowngeneral amino group and hydroxyl group deprotecting reaction.

Synthesis of Compound nc and Compound ne of Reference Example (See:Reference Examples 63 and 64)

(wherein X is halogen, M is boronic acid ester such as B(O-phenyl)₃etc., and other each symbol is same as above)

First Step

A compound nb can be obtained by adding a halogenating reagent (e.g.NBS, NCS, bromine etc.) to a compound na in a solvent such asdichloromethane, toluene, THF, dioxane etc., and performing a reactionfor 0.1 hours to 12 hours, preferably 0.2 hours to 6 hours under theoverheating refluxing condition.

Second Step

A compound nc can be obtained by subjecting the compound nb to the knowngeneral hydroxyl group deprotecting reaction.

Third Step

Boronic acid ester (R-M) corresponding to an objective substance isadded to a compound nb in a solvent such as toluene, THF, DMF etc. or ina mixed solvent thereof, and a base such as potassium carbonate, sodiumcarbonate, sodium hydroxide etc. is added. A 0-valent palladium catalyst(e.g.: Pd(PPh₃)₄) is added thereto under nitrogen stream, and a reactionis performed at 60° C. to 120° C., preferably 80° C. to 110° C. for 1hour to 48 hours, preferably 2 hours to 24 hours, thereby, a compound ndcan be obtained.

Fourth Step

A compound ne can be obtained by subjecting the compound nd to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound oh of Reference Example (See: Reference Example65)

(wherein R is a carboxyl protective group such as lower alkyl etc., R⁷is same as R^(7a) in item 1, L is a leaving group such as halogen, OMs,OTs etc., and other symbol is same as above)

First Step

A compound ob can be obtained by adding sodium chlorite andamidosulfuric acid to a compound oa in the presence of a solvent such asTHF, dioxane, dichloromethane, acetonitrile etc., and performing areaction at 0° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hours to24 hours, preferably 1 hour to 12 hours.

Second Step

A compound oc can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to the compound ob in the presence of a solvent suchas DMF, DMA, NMP, THF etc., adding amine (R³—NH₂) corresponding to anobjective substance, and tertiary amine such as triethylamine,N-methylmorpholine, pyridine etc., and performing a reaction at 10° C.to 60° C., preferably 20° C. to 40° C. for 0.1 hours to 24 hours,preferably 1 hour to 12 hours.

Third Step

A compound od can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound oc inthe presence of a solvent such as DMF, DMA, NMP, THF etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hours to 24 hours, preferably 1 hour to 12 hours.

Fourth Step

A compound oe can be obtained by adding R⁵—C(═O)—R⁶ and acetic acid tothe compound od in the presence of a solvent such as toluene, DMF, DMA,NMP, THF etc., and performing a reaction at 60° C. to 120° C.,preferably 80° C. to 110° C. for 0.1 hours to 24 hours, preferably 1hour to 12 hours.

Fifth Step

A compound of can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate etc. to the compound oe in thepresence of a solvent such as DMF, DMA, NMP, THF etc., and performing areaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hoursto 24 hours, preferably 1 hour to 12 hours.

Sixth Step

A compound og can be obtained by subjecting the compound of to the knowngeneral carboxyl group deprotecting reaction.

Seventh Step

A compound oh can be obtained by subjecting the compound og to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound pg of Reference Example (See: Reference Example95)

(wherein each symbol is same as above)

First Step

A compound pb can be obtained by adding aqueous ammonia to a compoundpa, and performing a reaction at 0° C. to 30° C., preferably 10° C. to30° C. for 0.5 hours to 48 hours, preferably 1 hour to 24 hours.

Second Step

A compound pc can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to the compound pb in the presence of a solvent suchas DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, adding amine(R³—NH₂) corresponding to an objective substance and, if necessary,tertiary amine such as triethylamine, N-methylmorpholine etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hours to 24 hours, preferably 1 hour to 12 hours.

Third Step

A compound pd can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound pc inthe presence of a solvent such as DMF, DMA, NMP, THF etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hours to 24 hours, preferably 1 hour to 12 hours.

Fourth Step

A compound pe can be obtained by adding R⁵—C(═O)—R⁶ and acetic acid tothe compound pd in the presence of a solvent such as toluene, DMF, DMA,NMP, THF etc., and performing a reaction at 60° C. to 120° C.,preferably 80° C. to 110° C. for 0.1 hours to 12 hours, preferably 0.2hours to 6 hours.

Fifth Step

A compound pf can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate etc. to the compound pe in thepresence of a solvent such as DMF, DMA, NMP, THF etc., and performing areaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hoursto 24 hours, preferably 1 hour to 12 hours.

Sixth Step

A compound pg can be obtained by subjecting the compound pf to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound qg, Compound qi, and Compound qk of ReferenceExample (See: Reference Example 128)

(wherein R represents a carboxyl protective group, n represents aninteger of 0 to 6, R^(Z7) and R^(Z8) are same as R^(C7) and R^(C8) initem 1, and other each symbol is same as above)

First Step

A compound qc can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to a compound qa in the presence of a solvent such aspyridine, DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, addinga compound qb and, if necessary, tertiary amine such as triethylamine,N-methylmorpholine etc., and performing a reaction at 10° C. to 60° C.,preferably 20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hourto 12 hours.

Second Step

A compound qd can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound qc inthe presence of a solvent such as DMF, DMA, NMP, THF etc. or in a mixedsolvent thereof, and performing a reaction at 10° C. to 60° C.,preferably 20° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hourto 24 hours.

Third Step

A compound pe can be obtained by adding R⁵—C(═O)—R⁶ and acetic acid tothe compound qd in the presence of a solvent such as toluene, DMF, DMA,NMP, THF etc. or in a mixed solvent thereof, and performing a reactionat 60° C. to 120° C., preferably 80° C. to 110° C. for 0.1 hours to 12hours, preferably 0.2 hours to 6 hours.

Alternatively, a compound qe can be obtained by performing a reaction at100° C. to 200° C. for 5 minutes to 1 hour under microwave irradiationcondition in a solvent such as ethanol, isopropyl alcohol etc.

Fourth Step

A compound qf can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate etc. to the compound qe in thepresence of a solvent such as DMF, DMA, NMP etc. or in a mixed solventthereof, and performing a reaction at 0° C. to 60° C., preferably 10° C.to 40° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.

Fifth Step

A compound qg can be obtained by subjecting the compound qf to the knowngeneral hydroxyl group deprotecting reaction.

Sixth Step

A compound qh can be obtained by subjecting the compound qf to the knowngeneral carboxyl group deprotecting reaction.

Seventh Step

A compound qi can be obtained by subjecting the compound qh to the knowngeneral hydroxyl group deprotecting reaction.

Eighth Step

A compound qj can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to a compound qh in the presence of a solvent such aspyridine, DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, addinga compound HNR^(Z7)R^(Z8) and, if necessary, tertiary amine such astriethylamine, diisopropylethylamine, N-methylmorpholine etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hours to 24 hours, preferably 1 hour to 12 hours.

Ninth Step

A compound qk can be obtained by subjecting the compound gj to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound qq of Reference Example, Compound qs of ReferenceExample, Compound qu of Reference Example, and Compound qw of ReferenceExample (see: Reference Example 128)

(wherein R^(Z2), R^(Z4), R^(Z9), R^(Z10), and R^(Z13) are same asR^(C2), R^(C4), R^(C9), R^(C10), and R^(C13) in item 1, and other eachsymbol is same as above)

First Step

A compound qm can be obtained by adding a condensation agent such asHATU, WSC.HCl, etc. to a compound qa in the presence of a solvent suchas pyridine, DMF, DMA, NMP etc. or in a mixed solvent thereof, adding acompound ql and, if necessary, tertiary amine such as triethylamine,diisopropylethylamine, N-methylmorpholine, etc., and performing areaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hoursto 24 hours, preferably 1 hour to 12 hours.

Second Step

A compound qn can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound qm inthe presence of a solvent such as DMF, DMA, NMP, THF etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.

Third Step

A compound pe can be obtained by adding R⁵—C(═O)—R⁶ and acetic acid tothe compound qn in the presence of a solvent such as toluene, DMF, DMA,NMP, THF etc. or in a mixed solvent thereof, and performing a reactionat 60° C. to 120° C., preferably 80° C. to 110° C. for 0.1 hours to 12hours, preferably 0.2 hours to 6 hours.

Alternatively, a compound qo can be obtained by performing a reaction at100° C. to 200° C. for 5 minutes to 1 hour under microwave irradiationcondition in a solvent such as ethanol etc.

Fourth Step

A compound qp can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate, etc. to the compound qo in thepresence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixedsolvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hourto 24 hours.

Fifth Step

A compound qq can be obtained by subjecting the compound qp to the knowngeneral hydroxyl group deprotecting reaction.

Sixth Step

A compound qr can be obtained by subjecting the compound qp to the knowngeneral amino group deprotecting reaction.

Seventh Step

A compound qs can be obtained by subjecting the compound qr to the knowngeneral hydroxyl group deprotecting reaction.

Eighth Step

A compound qt can be obtained by adding a compound R^(Z10)-Lcorresponding to an objective substance, and a base such as sodiumcarbonate, potassium carbonate, cesium carbonate, etc. to the compoundqr in the presence of a solvent such as DMF, DMA, NMP, THF, etc. or in amixed solvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hourto 24 hours.

Ninth Step

A compound qu can be obtained by subjecting the compound qt to the knowngeneral hydroxyl group deprotecting reaction.

Tenth Step

A base such as sodium carbonate, potassium carbonate, cesium carbonateetc. is added to the compound qr in the presence of a solvent such asTHF, dioxane, dichloromethane, acetonitrile, etc. A compound(R^(Z4)COCl, R^(Z2)SO₂C, or R^(Z13)OCOCl) corresponding to an objectivesubstance is slowly added thereto, and a reaction is performed at −20°C. to 60° C., preferably 0° C. to 30° C. for 0.1 hours to 48 hours,preferably 1 hour to 24 hours, thereby, a compound qv can be obtained.

Eleventh Step

A compound qw can be obtained by subjecting the compound qv to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound rb of Reference Example (See: Reference Example155)

(wherein each symbol is same as above)

A compound rb can be obtained by adding a compound R³NH₂ having asubstituent corresponding to an objective compound to a compound ra inthe presence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl,HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrile,etc. or in a mixed solvent thereof, and performing a reaction at −20° C.to 60° C., preferably −10° C. to 40° C. for 0.1 hours to 24 hours,preferably 1 hour to 12 hours. Alternatively, a compound rb can beobtained by adding an acylating reagent such as diphenylchlorophosphate,thionyl chloride, oxalyl chloride, etc. to a compound ra in the presenceor absence of a base such as pyridine, triethylamine,diisopropylethylamine, 1-methylimidazole, etc. in the presence of asolvent such as THF, dioxane, dichloromethane, DMF, etc. to generateacid chloride, adding a compound R³—NH₂ having a substituentcorresponding to an objective compound, and performing a reaction at−20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hours to 24hours, preferably 0.5 hours to 12 hours.

Synthesis of Compound sl of Reference Example (See: Reference Example49)

(wherein P³ is an amino protective group, and may be a group which canbe protected and/or deprotected by the method described in ProtectiveGroups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.and, for example, P³ is aryl lower alkyloxycarbonyl, loweralkylcarbonyl, etc. B is same as substituent group D in item 1, andother each symbol is same as above)

First Step

A compound sb can be obtained by adding an oxidizing reagent such asDess Martin Periodinane, manganese dioxide, PDC, etc, to a compound sain the presence of a solvent such as dichloromethane, THF, dioxane,toluene etc., and performing a reaction at −20° C. to 60° C., preferably0° C. to 40° C. for 0.1 hours to 24 hours, preferably 0.5 hours to 12hours.

Second Step

A compound sd can be obtained by adding sodium sulfate and anaminoalcohol sc corresponding to an objective substance to the compoundsb in the presence or absence of a solvent such as toluene, THF etc.,and performing a reaction at 0° C. to 80° C., preferably 20° C. to 60°C. for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours.

Third Step

A compound se can be obtained by subjecting the compound sd to the knowngeneral amino group deprotecting reaction.

Fourth Step

A compound sg can be obtained by adding a compound sf to the compound sein the presence of a solvent such as toluene, THF, dioxane etc., andperforming a reaction at 40° C. to 110° C., preferably 60° C. to 100° C.for 0.5 hours to 24 hours, preferably 1 hour to 12 hours.

Fifth Step

A compound sh can be obtained by subjecting the compound sg to the knowngeneral amino group deprotecting reaction and, thereafter, performing areaction at 40° C. to 110° C., preferably 60° C. to 100° C. for 0.1hours to 12 hours, preferably 0.2 hours to 6 hours in the presence of asolvent such as toluene, THF, dioxane, etc.

Sixth Step

A compound si can be obtained by subjecting the compound sh to the knowngeneral carboxyl group deprotecting reaction.

Seventh Step

A compound sj can be obtained by subjecting the compound si to the knowngeneral hydroxyl group deprotecting reaction.

Eighth Step

A decarbonized compound sk can be obtained by reacting the compound sifor 1 minute to 2 hours under microwave irradiation in a solvent such asdiphenyl ether etc.

Ninth Step

A compound sl can be obtained by subjecting the compound sk to the knowngeneral hydroxyl group deprotecting reaction.

Synthesis of Compound un of Reference Example (See: Reference Example177)

(wherein L¹ represents a leaving group such as halogen, OMs, OTs etc.,and other each symbol is same as above)

First Step

A compound ub can be obtained by subjecting a compound ua to a secondaryamino group protecting reaction.

Second Step

A compound uc can be obtained by subjecting the compound ub to a generalamino group protecting reaction.

Third Step

A compound ue can be obtained by adding a compound R⁷-L¹ correspondingto an objective compound to the compound uc in the presence of a solventsuch as DMF, DMA, NMP, etc. and a base such as NaH etc., and performinga reaction at 0° C. to 80° C., preferably 20° C. to 60° C. for 0.5 hoursto 12 hours, preferably 1 hour to 6 hours.

Fourth Step, Fifth Step

(wherein R³ and R⁷ may be bound adjacently and, in this case, a fourthstep and a fifth step are performed simultaneously)

A compound ue can be obtained by reacting a compound ud sequentiallywith compounds corresponding to an objective compound, R³-L and R7-L¹ inthe presence of a solvent such as DMF, DMA, NMP etc. and a base such asNaH etc.

Sixth Step

A compound ug can be obtained by subjecting a compound uf to a secondaryamino group protecting reaction.

Seventh Step

A compound uh can be obtained by subjecting the compound ug to asecondary amino group protecting reaction.

Eighth Step

A compound ue can be obtained by adding a base such as NaH etc. to thecompound uh in the presence of a solvent such as DMF, DMA, NMP,acetonitrile etc. or in a mixed solvent thereof, and performing areaction with a compound R³—Li corresponding to an objective compound.

Ninth Step

A compound uj can be obtained by subjecting the compound ue to a generalsecondary amine deprotecting reaction.

Tenth Step

A compound ul can be obtained by adding a condensation agent such asHATU, WSC.HCl etc. to a compound uk in the presence of a solvent such asDMF, DMA, THF, etc., adding amine uj corresponding to an objectivesubstance, and tertiary amine such as pyridine, triethylamine,N-methylmorpholine etc., and performing a reaction at 10° C. to 60° C.,preferably 20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hourto 12 hours.

Eleventh Step

A compound um can be obtained by subjecting the compound ul to a generalamino group protecting reaction.

Twelfth Step

A compound un can be obtained by adding R—C(═O)—R⁶, tertiary amine suchas, triethylamine, diisopropylethylamine, N-methylmorpholine, etc. andacetic acid, to the compound um in the presence of a solvent such astoluene, DMF, DMA, NMP etc., and performing a reaction at 60° C. to 120°C., preferably 80° C. to 100° C. for 0.1 hours to 24 hours, preferably 1hour to 12 hours.

Synthesis of Compound te of Reference Example

(wherein R′ may be a group which can be protected and/or deprotected bythe method described in Protective Groups in Organic Synthesis, TheodoraW Green (John Wiley & Sons) etc. and, for example, R′ is lower alkyletc. X is halogen, and other each symbol is same as above)

First Step

An alcohol (P¹—OH) corresponding to an objective substance is added toan organometallic base such as sodium tert-pentoxide, n-butyllithium,tert-butyllithium etc. in a solvent such as THF, ether, dichloromethane,DMI, DMF, DMA, etc. or in a mixed solution thereof. A solution of acompound ta is added dropwise thereto, and a reaction is performed at−20° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hours to 12 hours,preferably 0.5 hours to 6 hours, thereby, a compound tb can be obtained.

Second Step

A compound tc can be obtained by addingN,N-dimethylformamidodimethylacetal to the compound tb in a solvent suchas THF, dioxane, toluene, ethyl acetate etc. or in a mixed solventthereof, or without a solvent, and performing a reaction at 0° C. to 80°C., preferably 20° C. to 40° C. for 0.5 hours to 24 hours, preferably 1hour to 12 hours.

Third Step

A compound td corresponding to an objective substance is added to anorganometallic base such as sodium tert-pentoxide, n-butyllithium,tert-butyllithium, sodium metoxide, sodium ethoxide, sodiumtert-butoxide, potassium tert-butoxide etc. in a solvent such as THF,ether, DMI, methanol, ethanol, etc. or in a mixed solvent thereof. Asolution of the compound tc is added dropwise thereto, a reaction isperformed at −20° C. to 60° C., preferably 0° C. to 30° C. for 0.5 hoursto 24 hours, preferably 1 hour to 12 hours and, thereafter, an acid suchas hydrochloric acid, sulfuric acid etc. is added to perform a reactionat −20° C. to 60° C., preferably 0° C. to 30° C. for 0.5 hours to 24hours, preferably 1 hour to 12 hours, thereby, a compound te can beobtained.

Synthesis of Compound tm of Reference Example and Compound tp ofReference Example (See: Reference Examples 165, and 169)

(wherein R^(P) may be an acetal protective group which can protectand/or can be deprotected by the method described in Protective Groupsin Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. and, forexample, R^(P) is lower alkyl etc. Other each symbol is same as above)

First Step

A compound th can be obtained by adding allylamine to a compound tfwhich can be synthesized by the same method as that of a compound te inthe presence of a solvent such as ethanol, THF, dioxane, acetonitrile,etc. or in a mixed solvent thereof, and performing a reaction at 0° C.to 80° C., preferably 20° C. to 60° C. for 0.5 hours to 48 hours,preferably 1 hour to 24 hours.

Second Step

A compound ti can be obtained by adding a compound tg to a compound tfin the presence of a solvent such as ethanol, THF, dioxane, acetonitrileetc. or in a mixed solvent thereof, and performing a reaction at 0° C.to 80° C., preferably 20° C. to 60° C. for 0.5 hours to 48 hours,preferably 1 hour to 24 hours.

Third Step

A compound tj can be obtained by adding potassium osmate dihydrate,sodium periodate, and water to the compound th in the presence of asolvent such as THF, ethyl acetate, dioxane, etc. or in a mixed solventthereof, and performing a reaction at 0° C. to 60° C., preferably 10° C.to 40° C. for 0.5 hours to 24 hours, preferably 1 hour to 12 hours.

Alternatively, a compound tj can be obtained by introducing ozone intothe compound th at −10° C. to 20° C. in the presence of a solvent suchas THF, ethyl acetate, dioxane etc. or in a mixed solvent thereof and,subsequent to completion of the reaction, adding zinc-acetic acid,(EtO)₃P, or dimethyl sulfide.

Fourth Step

A compound tk can be obtained by adding an acid such as formic acid,trifluoroacetic acid, paratoluenesulfonic acid, etc. to the compound tiin a solvent such as acetone, acetonitrile, ethanol, water, etc. or in amixed solvent thereof, or adding sulfuric acid in a formic acid solvent,and performing a reaction at 0° C. to 90° C., preferably 20° C. to 80°C. for 0.5 hours to 24 hours, preferably 1 hour to 12 hours.

Fifth Step

A compound tm can be obtained by adding a compound tl and acetic acid tothe compound tj or the compound tk in the presence of a solvent such aschloroform, dichloromethane, THF, etc., and performing a reaction at 0°C. to 40° C., preferably 10° C. to 30° C. for 0.5 hours to 24 hours,preferably 1 hour to 12 hours.

Sixth Step

A compound to can be obtained by adding a compound tn and acetic acid tothe compound tj or the compound tk in the presence of a solvent such aschloroform, dichloromethane, THF, etc., and performing a reaction at 0°C. to 40° C., preferably 10° C. to 30° C. for 0.5 hours to 24 hours,preferably 1 hour to 12 hours.

Seventh Step

A compound tp can be obtained by adding a compound B—Li corresponding toan objective compound to the compound to in the presence of a solventsuch as DMF, DMA, NMP, THF, etc. or in a mixed solvent thereof, andperforming a reaction at 0° C. to 80° C., preferably 20° C. to 60° C.for 0.5 hours to 12 hours, preferably 1 hour to 6 hours.

Synthesis of Compound vf of Reference Example (See: Reference Examples583, and 584)

(wherein Y1 is a substituent corresponding to R^(3a), and Y2 is asubstituent corresponding to R^(11a). Other each symbol is same asabove)

First Step

A compound vc can be obtained by adding a compound vb having asubstituent corresponding to an objective compound to a compound va inthe presence of a dehydration-condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimido-N-hydroxybenzotriazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,hexafluorophosphoric acid2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl,HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrileetc. or in a mixed solvent thereof, and performing a reaction at −20° C.to 60° C., preferably −10° C. to 40° C. for 0.1 hours to 24 hours,preferably 1 hour to 12 hours.

Alternatively, a compound vc can be obtained by adding an acylatingreagent such as diphenylchlorophosphate, thionyl chloride, oxalylchloride etc. to a compound va in the presence or absence of a base suchas pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole,etc. in the presence of a solvent such as THF, dioxane, dichloromethane,DMF etc., thereby, generating acid chloride, and adding a compound vbhaving a substituent corresponding to an objective compound, andperforming a reaction at −20° C. to 60° C., preferably −10° C. to 40° C.for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours.

Second Step

A compound vd can be obtained by adding potassium carbonate, sodiumcarbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound vc inthe presence of a solvent such as DMF, DMA, NMP, THF, etc., andperforming a reaction at 10° C. to 60° C., preferably 20° C. to 40° C.for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.

Third Step

A deprotecting reaction of an acetal protective group of the compound vdcan be performed by the general method described in Protective Groups inOrganic Synthesis, Theodora W Green (John Wiley & Sons) etc. Thereafter,a generated aldehyde group is subjected to an intramolecular reaction,thereby, a compound ve can be obtained.

For example, a compound ve can be obtained by adding acetic acid and/orparatoluenesulfonic acid to the compound vd in the presence of a solventsuch as DMF, toluene, THF, etc., and performing a reaction at 10° C. to80° C., preferably 30° C. to 60° C. for 0.5 hours to 12 hours,preferably 1 hour to 6 hours.

Fourth Step

A compound vf can be obtained by adding a compound R⁷-L¹ correspondingto an objective substance, and a base such as sodium carbonate,potassium carbonate, cesium carbonate, etc. to the compound ye in thepresence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixedsolvent thereof, and performing a reaction at 0° C. to 60° C.,preferably 10° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hourto 24 hours.

Synthesis of Compound wd of Reference Example (See: Reference Example592, Etc.)

(wherein each symbol is same as above, and P¹ may be a group which canbe protected and/or deprotected by the method described in ProtectiveGroups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.and, for example, P¹ is arylalkyl, etc.)

First Step

A compound wb can be obtained by adding a cation-forming reagent (e.g.:dichloroacetic acid) to the compound wa in the presence of a solventsuch as 1,2-dichloroethane, THF, dioxane, chloroform, etc. and adding areagent, R⁷—OH corresponding to an objective substance, and performing areaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hoursto 24 hours, preferably 0.5 hours to 12 hours.

Second Step

A base (e.g.:2-tert-butylimino2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine)is added to the compound wb in the presence of a solvent such as DMF,DMA, NMP, THF, etc., paraformaldehyde is added, and they are reacted at0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hours to 24 hours,preferably 0.5 hours to 12 hours. Next, a compound we can be obtained byadding a detachment reagent (e.g.: p-toluenesulfonyl chloride), andperforming a reaction at 0° C. to 60° C., preferably 10° C. to 40° C.for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours.

Synthesis of Compound of Example (Prodrug: Formula (I)) from Compound ofReference Example (Parent Compound: Formula (II)) (See: Examples 1, 98,105, 106, 106, 107, 108, 111, 112, 113, 122, 151, 152, 163, 177, 178,186, 190, 192, 194, 196, 197, 199, 200, 201, and 203)

(wherein each substituent is same as in item 1)

A compound of Example can be obtained by the general method includingconverting a hydroxyl group into an ester group or ether group, using acompound shown in Reference example as a source.

For example, the method described in Protective Groups in OrganicSynthesis, Theodora W Green (John Wiley & Sons), Prog. Med. 5: 2157-2161(1985), and Supplied by The British Library—“The world's Knowledge”,etc. can be utilized.

The present invention will be explained in more detail below by way ofExamples, Reference examples, Intermediate Synthesis Examples, as wellas Test Examples of the present invention, but the present invention isnot limited by them.

Hereinbelow, structural formulae of compounds of Reference examples 1 to775 that are parent compounds, and Synthesis Examples are shown.

Reference Example 1

First Step

A dichloromethane (90 mL) solution of compound 1A (12.8 g, 89.4 mmol)and pyridine (8.50 g, 107 mmol) was cooled to 1 to 3° C., and adichloromethane (90 mL) solution of benzyloxyacetyl chloride (19.8 g,107 mmol) was added dropwise over 50 minutes while the same temperaturewas retained. After the reaction solution was stirred at the sametemperature for 30 minutes, temperature was gradually raised to 15° C.over 60 minutes, and ice water was added. The dichloromethane layer wasseparated, and the aqueous layer was extracted with dichloromethaneonce. The combined extracts were washed with water three times, washedwith an aqueous saturated sodium chloride solution, and dried. Thesolvent was distilled off, and the resulting oil was purified by silicagel column chromatography. The materials were eluted firstly withn-hexane and, then, with n-hexane-ethyl acetate (1:1, v/v).Concentration of objective fraction afforded 22.2 g of compound 1B as anoil.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 2.90 (3H, brs), 3.24 (3H,brs), 4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.58 (2H, s), 7.25-7.38 (5H,m), 7.72 (1H, s).

Second Step

A 1N lithiumhexamethyldisilazane THF solution (4.29 ml, 4.29 mmol) wascooled to −78° C., and a THF solution (4 ml) of compound 1B (500 mg,1.72 mmol) and cinnamoyl chloride (343.2 mg, 2.06 mmol) were addeddropwise thereto over 3 minutes while the same temperature was retained.After the reaction solution was stirred at the same temperature for 25minutes, 2N hydrochloric acid (10 ml) was added, and the mixture wasfurther stirred at room temperature for 10 minutes. To the reactionsolution was added ethyl acetate, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate three times. Thecombined extracts were dried with sodium sulfate. The solvent wasdistilled off, and the resulting oil was purified by silica gel columnchromatography. From fraction eluted with n-hexane-ethyl acetate (1:1,v/v), 364.3 mg (yield 56%) of compound 1C was obtained as a solid.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.2 Hz), 4.39 (2H, q, J=7.2 Hz), 5.27(2H, s), 6.99 (1H, d, J=16.2 Hz), 7.23 (1H, d, J=16.2), 7.26-7.48 (10H,m), 8.45 (1H, s).

Third Step

To a MeCN (5 ml) solution of compound 1C and ruthenium chloride (2.76mg, 0.0133 mmol) was added dropwise an aqueous solution (8 ml) of sodiumperiodate (625.8 mg, 2.93 mmol) and 96% sulfuric acid (287.4 mg, 2.93mmol) over 10 minutes at room temperature under nitrogen stream. Afterthe reaction solution was stirred at the same temperature for 5 minutes,ethyl acetate was added, the organic layer was separated, and theaqueous layer was extracted with ethyl acetate two times. The combinedextracts were dried with sodium sulfate. The solvent was distilled off,and the resulting oil was purified by silica gel column chromatography.From fraction eluted with n-hexane-ethyl acetate (1:1, v/v), 303.2 mg(yield 75%) of compound 1D was obtained as an oil.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=6.9 Hz), 4.40 (2H, q, J=6.9 Hz), 5.54(2H, s), 7.37 (5H, s), 8.48 (1H, s), 9.85 (1H, s).

Fourth Step

To a MeCN (15 ml) solution of compound 1D (1.00 g, 3.31 mmol) was addedan aqueous solution (10 ml) of 96% sulfuric acid (421.7 mg, 4.30 mmol)and amidosululic acid (642.7 mg, 6.62 mmol) at room temperature, themixture was stirred, and an aqueous solution (10 ml) of sodium chlorite(388.9 mg, 4.30 mmol) was added dropwise over 5 minutes while the sametemperature was retained. After the reaction solution was stirred at thesame temperature for 5 minutes, an aqueous saturated sodium chloridesolution was added, and the mixture was extracted with ethyl acetatethree times. The combined extracts were dried with sodium sulfate. Thesolvent was distilled off, and the resulting oil was purified by silicagel column chromatography. The materials were eluted firstly withchloroform and, then, with chloroform-MeOH (7:3, v/v). Concentration ofobjective fraction afforded 748.8 mg (yield 71%) of compound 1E as anoil.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.2 Hz), 3.93 (1H, brs), 4.40 (2H, q,J=7.2 Hz), 5.61 (2H, s), 7.38-7.44 (10H, m), 8.52 (1H, s).

Fifth Step

To a DMF (10 ml) solution of compound 1E (1.00 g, 3.14 mmol) were addedWSC HCl(1.20 g, 6.28 mmol) and HOBt (551.6 mg, 4.08 mmol) at roomtemperature, and the mixture was stirred at the same temperature for 90minutes. The reaction solution was cooled to 0° C., and a DMF (2 ml)solution of 2-methoxyethanamine (236.0 mg, 3.14 mmol) was added dropwiseover 3 minutes. The reaction solution was stirred at the sametemperature for 1 hour, water was added, and the mixture was extractedwith ethyl acetate three times. The extract was washed with water threetimes, and dried with sodium sulfate. The solvent was distilled off, andthe resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with n-hexane-ethyl acetate (1:1, v/v)and, then, with n-hexane-ethyl acetate (1:9, v/v). Concentration ofobjective fraction afforded 928.5 mg (yield 79%) of compound 1F as anoil.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.2 Hz), 3.29 (3H, s), 3.41 (2H, t,J=5.4 Hz), 3.47-3.53 (2H, m), 4.39 (2H, q, J=7.2 Hz), 5.44 (2H, s), 7.36(3H, m), 7.44-7.47 (2H, m), 8.07 (1H, brs), 8.54 (1H, s).

Sixth Step

A xylene (2 ml) solution of compound 1F (500 mg, 1.33 mmol) and(S)-2-amino-3-phenylpropan-1-ol (604.2 mg, 4.0 mmol) was heated to 120°C., and stirred for 30 minutes. After the reaction solution was cooledto room temperature, and the solvent was distilled off, the resultingoil was purified by silica gel chromatography. The materials were elutedfirstly with chloroform and, then, with chloroform-MeOH (9:1, v/v).Concentration of objective fraction afforded 487 mg (yield 72%) ofcompound 1G as an oil.

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=6.9 Hz), 2.24-2.34 (1H, m), 2.24-3.00(1H, m), 3.03-3.16 (1H, m), 3.05 (3H, m), 3.25-3.32 (2H, m), 4.13-4.19(1H, m), 4.17-4.30 (1H, m), 4.36-4.47 (1H, m), 4.51-4.54 (1H, m), 4.55(1H, d, J=10.5 Hz), 5.78 (1H, t, J=6.9 Hz), 7.17-7.26 (4H, m), 7.28-7.35(5H, m), 7.49 (1H, t, J=5.4 Hz), 6.32 (1H, s).

Seventh Step

To a THF (6 ml) solution of compound 1G (2.86 g, 5.63 mmol) andtriphenylphosphine (2.21 g, 8.45 mmol) was added dropwise a DEAD 40 wt %toluene solution (3.68 g, 8.45 mmol) at room temperature over 3 minutes.The reaction solution was stirred at the same temperature for 30minutes, the solvent was distilled off, and the resulting oil waspurified by silica gel chromatography. From a fraction eluted with ethylacetate-MeOH (9:1, v/v), 1.37 g (yield 50%) of compound 1H was obtainedas an oil.

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 3.07 (2H, d, J=6.9 Hz), 3.33(3H, s), 3.57-3.80 (4H, m), 3.95 (1H, dd, J=3.0 Hz, 6.6 Hz), 4.01-4.14(1H, m), 4.16-4.34 (2H, m), 5.24 (1H, d, J=9.9 Hz), 5.51 (1H, d, J=9.9Hz), 7.01-7.03 (2H, m), 7.21-7.37 (5H, m), 7.41-7.58 (1H, m), 7.64-7.69(2H, m).

Eighth Step

To an EtOH (6 ml) solution of compound 1H (1.0 g, 2.04 mmol) was added a2N aqueous sodium hydroxide solution (6 ml), and the mixture was stirredat room temperature for 30 minutes. The reaction solution wasneutralized with 2N hydrochloric acid, and the precipitated solid wasfiltered, and dried to obtain 754 mg (yield 80%) of compound 11.

¹H-NMR (CDCl₃) δ: 3.10 (2H, d, J=7.8 Hz), 3.33 (3H, s), 3.57-3.69 (4H,m), 3.82-3.90 (1H, m), 3.95 (1H, dd, J=3.3 Hz, 13.8 Hz), 4.36 (1H, dd,J=6.3 Hz, 7.5 Hz), 5.36 (1H, d, J=10.2 Hz), 5.45 (1H, d, J=10.2 Hz),6.98-7.01 (2H, m), 7.28-7.39 (6H, m), 7.59 (2H, dd, J=1.8 Hz, 8.1 Hz),7.87 (1H, s).

Ninth Step

Compound 1I (1.0 g, 2.16 mmol) was dissolved in THF (10 ml), 10% Pd—C(200 mg) was added, and the mixture was subjected to a catalyticreduction reaction under hydrogen stream. The catalyst was removed byfiltration, and the filtrate was concentrated. The resulting residue waswashed with ether to obtain 512 mg (yield 64%) of compound 1.

¹H-NMR (CDCl₃) δ: 6.24 (2H, d, J=6.3 Hz), 3.36 (3H, s), 3.60-3.86 (5H,m), 4.14 (1H, d, J=12.9 Hz), 4.47 (1H, s), 7.03-7.05 (2H, m), 7.30-7.35(3H, m), 7.88 (1H, s), 12.68 (1H, s), 14.83 (1H, s).

Reference Example 2

First Step

To (S)-tert-butyl 3-hydroxy-1,1-diphenylpropan-2-ylcarbamate (5.00 g,15.3 mmol) was added trifluoroacetic acid (40 ml), and the mixture wasstirred for 1 hour under ice-cooling. After trifluoroacetic acid wasdistilled off, toluene was added, and distilled off again under reducedpressure to obtain crude (S)-2-amino-3,3-diphenylpropan-1-ol. To theresulting (S)-2-amino-3,3-diphenylpropan-1-ol were added compound 1F(5.73 g, 15.3 mmol), toluene (50 ml), and triethylamine (6.4 ml, 45.8mmol), the mixture was stirred at 90° C. for 1 hour, and cooled to roomtemperature and, thereafter, the solvent was distilled off. To theresulting residue was added dichloromethane, and the mixture was washedwith 2N aqueous hydrochloric acid solution, an aqueous saturated sodiumbicarbonate solution, and an aqueous saturated sodium chloride solution.After separation of the organic layer, after magnesium sulfate wasadded, the mixture was filtered with celite, and the filtrate wasdistilled off to obtain candy-like compound 2A (9.12 g).

MS: m/z=585.2 [M+H]+.

Second Step

The compound 2A (8.60 g, 14.7 mmol) and triphenylphosphine (7.72 g, 29.4mmol) were dissolved in tetrahydrofuran (90 ml), and a 2.2M toluenesolution of diethyl azodicarboxylate (10.0 ml, 22.0 mmol) was addeddropwise under ice-cooling. After the mixture was stirred for 2 hoursunder ice-cooling, and for 18 hours under room temperature, the solventwas distilled off. The resulting residue was purified by silica gelcolumn chromatography to obtain foamy compound 2B (3.88 g, 6.85 mmol).

¹H-NMR (DMSO-d₆) δ: 1.18 (3H, m), 3.11 (3H, s), 3.16 (1H, m), 3.28 (1H,m), 3.76 (1H, m), 3.97-4.13 (3H, m), 4.31 (1H, d, J=11.3 Hz), 5.08 (2H,s), 5.52 (1H, d, J=12.0 Hz), 7.18-7.25 (6H, m), 7.25-7.45 (6H, m),7.55-7.66 (6H, m).

MS: m/z=567.7 [M+H]⁺.

Third Step

To compound 2B (3.4 g, 6.0 mmol) were added ethanol (36 ml), water (12ml), and a 2N aqueous sodium hydroxide solution (4.5 ml, 9.0 mmol), andthe mixture was stirred at room temperature for 40 minutes, thereafter,ethanol (10 ml) and water (10 ml) were added, and the mixture wasfurther stirred for 30 minutes. Ethanol was distilled off, ethyl acetateand water were added, and the mixture was stirred vigorously and,thereafter, layers were separated. The ethyl acetate layer was washedwith 2N sodium hydroxide three times, and the aqueous layers werecombined into one aqueous layer. To the aqueous layer was added ethylacetate, the mixture was neutralized using 2N hydrochloric acid, thenthe mixture was stirred vigorously and, thereafter, the ethyl acetatelayer was separated. To the ethyl acetate layer was added magnesiumsulfate, the mixture was filtered with celite, and the filtrate wasdistilled off. The resulting residue was dissolved in MeOH, and thesolvent was distilled off to obtain a solid of compound 2C (3.0 g, 5.64mmol).

¹H-NMR (DMSO-d₆) δ: 3.11 (3H, s), 3.16 (1H, m), 3.25 (1H, m), 3.75 (1H,m), 4.11 (1H, m), 4.36 (1H, d, J=11.6 Hz), 5.18 (2H, dd, J=15.7 Hz, 10.4Hz), 5.71 (1H, d, J=11.6 Hz), 7.08-7.20 (5H, m), 7.29-7.45 (6H, m), 7.55(2H, d, J=6.7 Hz), 7.61 (2H, d, J=7.5 Hz), 7.98 (1H, s).

MS: m/z=539.4 [M+H]⁺.

Fourth Step

To compound 2C (1.50 g, 2.79 mmol) were added methanol (22 ml), and 10%palladium carbon-50% wet (150 mg), and the mixture was stirred for 1hour under hydrogen atmosphere. Ethyl acetate (44 ml) was added, themixture was filtered with celite, and the filtrate was distilled off.The resulting residue was dissolved in methanol (20 ml), water (10 ml)was added, and methanol was distilled off. The precipitate was filtered,and dried to obtain compound 2 (1.15 g, 2.56 mmol).

¹H-NMR (DMSO-d₆) δ: 3.15 (3H, s), 3.50-3.70 (5H, m), 4.19 (1H, dd,J=13.8 Hz, 3.1 Hz), 4.49 (1H, d, J=11.6 Hz), 5.78 (1H, d, J=9.6 Hz),7.10-7.27 (6H, m), 7.34 (1H, m), 7.46 (2H, t, J=7.5 Hz), 7.63 (2H, t,J=7.7 Hz), 7.94 (1H, s), 12.94 (1H, s), 15.08 (1H, s).

MS: m/z=449.4 [M+H]⁺.

Reference Example 3

According to Reference example 2, compound 3 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.15 (1H, m), 3.26 (3H, s), 3.52-3.70 (4H, m),3.70-3.80 (2H, m), 4.10 (1H, d, J=12.9 Hz), 4.92 (1H, brs), 6.98 (1H, t,J=7.4 Hz), 7.03 (1H, brs), 7.08 (1H, t, 7.6 Hz), 7.34 (1H, d, J=7.8 Hz),7.47 (1H, d, J=7.3 Hz), 7.80 (1H, s), 10.94 (1H, brs), 15.38 (1H, brs).

MS: m/z=412.4 [M+H]⁺.

Reference Example 4

According to Reference example 2, compound 4 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.13 (3H, s), 3.46-3.72 (5H, m), 4.16 (1H, d, J=12.6Hz), 4.48 (1H, d, J=10.9 Hz), 5.77 (1H, d, J=11.6 Hz), 7.10-7.27 (6H,m), 7.32 (1H, m), 7.44 (2H, m), 7.61 (2H, m), 7.93 (1H, s), 15.04 (1H,s).

MS: m/z=449.3 [M+H]⁺.

Reference Example 5

According to Reference example 2, compound 5 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.28 (3H, s), 3.52-3.68 (4H, m), 4.06 (1H, m), 4.25(2H, m), 4.41 (1H, brs), 4.56 (1H, d, J=13.6 Hz), 4.82 (1H, d, J=13.9Hz), 6.74 (2H, d, J=7.6 Hz), 6.92 (1H, t, J=7.20 Hz), 7.25 (2H, t, J=7.8Hz), 8.58 (1H, s), 12.48 (1H, brs), 15.55 (1H, brs).

MS: m/z=389.4 [M+H]⁺.

Reference Example 6

According to Reference example 2, compound 6 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 3.16 (1H, m), 3.26 (3H, s), 3.50-3.70 (4H, m),3.70-3.80 (2H, m), 4.10 (1H, d, J=13.4 Hz), 4.92 (1H, brs), 6.98 (1H, t,J=7.1 Hz), 7.03 (1H, brs), 7.08 (1H, t, J=7.3 Hz), 7.34 (1H, d, J=7.8Hz), 7.48 (1H, d, J=7.3 Hz), 7.81 (1H, s), 12.91 (1H, s), 15.36 (1H, s).

MS: m/z=412.4 [M+H]⁺.

Reference Example 7

According to Reference example 2, compound 7 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 0.85-0.95 (2H, m), 1.05-1.25 (5H, m), 1.45-1.80 (8H,m), 3.28 (3H, s), 3.46 (1H, m), 3.58 (1H, m), 3.72 (1H, d, J=13.9 Hz),3.93 (1H, m), 4.04 (1H, d, J=13.1 Hz), 4.88 (1H, s), 8.56 (1H, s), 12.80(1H, s), 15.51 (1H, s).

MS: m/z=379.3 [M+H]⁺.

Reference Example 8

According to Reference example 2, compound 8 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.07 (2H, m), 2.55 (1H, m), 2.74 (1H, m), 3.17 (1H,s), 3.23 (3H, s), 3.48-3.65 (4H, m), 3.79 (1H, d, J=13.6 Hz), 3.87 (1H,m), 4.09 (1H, d, J=13.6 Hz), 4.80 (1H, s), 7.10-7.29 (5H, m), 8.59 (1H,s), 12.77 (1H, s), 15.49 (1H, s).

MS: m/z=387.3 [M+H]⁺.

Reference Example 9

According to Reference example 2, compound 9 was synthesized by the sameprocedure.

¹H-NMR (DMSO-d₆) δ: 2.80 (1H, dd, J=14.5 Hz, J2=8.5 Hz), 2.93 (1H, dd,J=14.4 Hz, 5.6 Hz), 3.21 (3H, s), 3.40-3.55 (4H, m), 3.77 (2H, s), 3.82(1H, d, J=13.1 Hz), 3.88 (1H, m), 4.13 (1H, d, J=13.6 Hz), 4.85 (1H, s),7.20-7.35 (5H, m), 8.61 (1H, s), 12.79 (1H, s), 15.43 (1H, s).

MS: m/z=419.3 [M+H]⁺.

Reference Example 10

According to Reference example 2, compound 10 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, d, J=6.2 Hz), 3.29 (3H, s), 3.43 (1H, m),3.58 (2H, m), 3.94 (1H, m), 4.12 (1H, brs), 4.41 (1H, d, J=13.6 Hz),4.49 (1H, d, J=13.1 Hz), 8.59 (1H, s), 12.65 (1H, s), 15.53 (1H, s).

MS: m/z=297.2 [M+H]⁺.

Reference Example 11

According to Reference example 2, compound 11 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.46 (4H, brs), 1.76-1.90 (2H, m), 2.22 (1H, brs),3.27 (3H, s), 3.57 (1H, d, J=5.3 Hz), 4.07 (1H, m), 4.69 (1H, m), 8.47(1H, s), 13.04 (1H, s), 15.52 (1H, s).

MS: m/z=337.2 [M+H]⁺.

Reference Example 12

First Step

Compound 12A (1.53 g, 5.80 mmol) were dissolved in THF (6 ml) and water(6 ml), potassium carbonate (2.41 g, 17.4 mmol) was added, the mixturewas stirred, and benzyl chloroformate (1.09 g, 6.38 mmol) was addeddropwise at 0° C. After stirring at 0° C. for 10 minutes, the mixturewas stirred at room temperature for 2 hours. The reaction solution waspoured into sodium bicarbonate water, and the mixture was extracted withethyl acetate. The extract was washed with 1N hydrochloric acid and anaqueous saturated sodium chloride solution, and dried with sodiumsulfate. The solvent was distilled off to obtain 2.32 g of compound 12Bas a colorless gummy substance.

¹H-NMR (CDCl₃) δ: 1.98 (1H, brs), 3.55 (1H, m), 3.75 (1H, m), 4.20 (1H,d, J=10.5 Hz), 4.58 (1H, m), 4.83 (1H, brs), 5.07 (2H, s), 7.16-7.39(15H, m).

Second Step

The compound 12B (1.94 g, 5.37 mmol), triphenylphosphine (2.11 g, 8.05mmol) and phthalimide (948 mg, 6.44 mmol) were added to THF (20 ml), anddiisopropyl azodicarboxylate (2.2M in toluene, 3.66 ml, 8.05 mmol) wasadded dropwise at room temperature. After stirring at room temperaturefor 4 hours, the solvent was distilled off under reduced pressure. Theresulting crude product was purified by silica gel column chromatography(n-hexane-ethyl acetate, 1:1, v/v) to obtain 2.39 g of compound 12C as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.73 (2H, m), 4.05 (1H, d, J=10.1 Hz), 4.70 (1H, d,J=9.6 Hz), 4.77 (2H, d, J=7.2 Hz) 5.02 (1H, m), 7.03-7.42 (15H, m), 7.68(2H, dd, J=5.7, 2.1 Hz), 7.78 (2H, dd, J=5.7, 2.1 Hz).

Third Step

The compound 12C (2.39 g, 4.87 mmol) was added to THF (20 ml) andmethanol (20 ml), hydrazine hydrate (4.88 g, 97.4 mmol) was added, andthe mixture was stirred at 50° C. for 4 hours. The white precipitate wasremoved by filtration, and washed with methanol. After the filtrate wasdistilled off under reduced pressure, the resulting crude product waspurified by amino column chromatography (chloroform-methanol, 99:1, v/v)to obtain 1.41 g of compound 12D as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.63 (1H, dd, J=13.2, 5.8 Hz), 2.86 (1H, d, J=9.9 Hz),4.07 (1H, d, J=10.4 Hz), 4.53 (1H, m), 4.81 (1H, m), 5.00 (2H, d, 8.4Hz), 7.20-7.36 (10H, m).

Fourth Step

Compound 12D (1.41 g, 3.91 mmol) was dissolved in THF (15 ml), and Boc2O(896 mg, 4.11 mmol) was added at room temperature. After stirring for1.5 hours, the solvent was concentrated under reduced pressure. Theresulting crude product was purified by silica gel column chromatography(n-hexane-ethyl acetate, 1:1, v/v) to obtain 1.77 g of compound 12E as acolorless solid.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 3.23 (2H, brm), 3.97 (1H, d, J=9.8 Hz),4.58-4.80 (3H, m), 5.00 (2H, d, J=9.8 Hz), 7.15-7.29 (10H, m).

Fifth Step

Compound 12E (1.73 g, 3.76 mmol) and palladium-active carbon (10%, wet,200 mg) were added to methanol (20 ml), and the mixture was stirred atroom temperature for 1 hour under hydrogen atmosphere. After filtrationwith celite, the solvent was concentrated under reduced pressure toobtain 1.01 g of a colorless oily substance 12F.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.82 (1H, m), 3.31 (1H, m), 3.73 (2H, d,J=6.9 Hz), 4.98 (1H, s), 7.18-7.39 (10H, m).

Sixth Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (974 mg, 3.06mmol) obtained by the method shown in Intermediate Synthesis Example 1,and 12F (999 mg, 3.06 mmol) were added to toluene (10 ml), and themixture was stirred at 110° C. for 5 hours. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol, 98:2,v/v) to obtain 1.51 g of compound 12G as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 1.36 (9H, s), 3.40 (1H, m), 3.53 (1H, m), 3.82 (3H,s), 3.91 (3H, s), 4.29 (1H, d, J=11.3 Hz), 4.78 (1H, m), 4.82 (1H, m),5.11 (1.9H, d, J=7.5 Hz), 7.10-7.38 (10H, m), 8.27 (1H, s).

Seventh Step

To compound 12G (1.45 g, 2.31 mmol) was added 4N HCl (ethyl acetatesolution, 20 ml), and the mixture was stirred at room temperature for1.5 hours. After the solvent was distilled off under reduced pressure,sodium bicarbonate water was added, and the mixture was stirred at roomtemperature for 1.5 hours. This was extracted with chloroform, and driedwith sodium sulfate. After the solvent was distilled off under reducedpressure, the resulting crude product was purified by silica gel columnchromatography (chloroform-methanol, 95:5, v/v) to obtain 1.01 g ofcompound 12H as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.40 (1H, dd, J=13.6, 6.6 Hz), 3.78 (3H, s), 3.80 (1H,m), 4.37 (1H, d, J=11.6 Hz), 4.59 (1H, d, J=11.0 Hz), 5.43 (2H, d,J=10.2 Hz), 5.93 (1H, d, J=5.8 Hz), 7.03-7.21 (5H, m), 7.37 (9H, m),7.63 (2H, m).

Eighth Step

Compound 12H (50 mg, 0.10 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (165 mg, 0.50 mmol) was added. After stirring at roomtemperature for 30 minutes, iodomethane (0.032 ml, 0.50 mmol) was added,and the mixture was stirred at room temperature for 3.5 hours. Thereaction solution was poured into water, and the mixture was extractedwith ethyl acetate, and dried with sodium sulfate. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol, 95:5,v/v) to obtain 49 mg of compound 121 as a colorless solid.

Ninth Step

Compound 121 (49 mg, 0.096 mmol) was dissolved in THF (0.5 ml) andmethanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.24 ml, 0.48mmol) was added at room temperature, and the mixture was stirred for 1.5hours. After 1N hydrochloric acid was added, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, 54 mg ofcompound 12J was obtained as a colorless solid.

MS: m/z=481 [M+H]⁺.

Tenth Step

To compound 12J obtained in the ninth step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 3 withsodium bicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 26 mg of compound 12 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 3.01 (3H, s), 3.26 (1H, t, J=14.4 Hz), 4.23 (1H, dd,J=13.5, 3.8 Hz), 4.57 (1H, d, J=11.6 Hz), 5.78 (1H, d, J=11.3 Hz),7.16-7.70 (10H, m), 8.00 (1H, s), 13.00 (1H, s), 15.10 (1H, s).

MS: m/z=405 [M+H]⁺.

Reference Example 13

According to Reference example 12, compound 13 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.05 (3H, t, J=6.9 Hz), 3.43-3.65 (3H, m), 4.22 (1H,d, J=10.6 Hz), 4.55 (1H, d, J=11.6 Hz), 5.81 (1H, d, J=10.1 Hz),7.15-7.68 (10H, m), 7.97 (1H, s), 12.96 (1H, s), 15.07 (1H, s).

MS: m/z=463 [M+H]⁺.

Reference Example 14

According to Reference example 12, compound 14 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 0.98 (3H, t, J=7.17 Hz), 3.44-3.64 (3H, m), 4.15(1H, dd, J=13.7, 3.5 Hz), 4.45 (1H, d, J=11.6 Hz), 5.79 (1H, d, J=12.2Hz), 7.08-7.63 (10H, m), 7.89 (1H, s), 13.01 (1H, s), 15.06 (1H, s).

MS: m/z=419 [M+H]⁺.

Reference Example 15

According to Reference example 12, compound 15 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.22 (1H, s), 3.47 (1H, d, J=13.3 Hz), 4.17 (2H, m),4.44 (2H, dd, J=16.7, 3.0 Hz), 5.79 (1H, d, J=12.2 Hz), 7.10-7.64 (10H,m), 7.98 (1H, s), 12.56 (1H, s), 15.05 (1H, brs).

Reference Example 16

According to Reference example 12, compound 16 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.24 (1H, d, J=13.2 Hz), 4.23 (1H, m), 4.25 (1H, d,J=14.7 Hz), 4.40 (1H, d, J=14.8 Hz), 4.92 (1H, d, J=15.4 Hz), 5.79 (1H,m), 7.03-7.48 (10H, m), 7.93 (1H, s), 12.82 (1H, s), 15.06 (1H, s).

Reference Example 17

According to Reference example 12, compound 17 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.23 (1H, d, J=13.4 Hz), 4.22 (1H, m), 4.25 (1H, d,J=12.0 Hz), 4.45 (1H, d, J=14.9 Hz), 4.93 (1H, d, J=15.3 Hz), 5.77 (1H,d, J=11.6 Hz), 7.09-7.56 (10H, m), 7.92 (1H, s), 12.74 (1H, s), 15.06(1H, s).

Reference Example 18

According to Reference example 12, compound 18 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.63 (2H, m), 3.20 (3H, s), 3.44 (5H, m), 4.19 (1H,d, J=10.2 Hz), 4.51 (1H, d, J=11.8 Hz), 5.80 (1H, d, J=11.0 Hz),7.13-7.65 (10H, m), 7.93 (1H, s), 13.02 (1H, s).

MS: m/z=463 [M+H]⁺.

Reference Example 19

According to Reference example 12, compound 19 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.15 (1H, d, J=9.5 Hz), 3.95 (1H, dd, J=13.5, 3.4Hz), 4.51 (1H, d, J=11.6 Hz), 5.74 (1H, d, J=11.1 Hz), 7.11-7.62 (10H,m), 7.93 (1H, s), 9.34 (1H, s), 12.97 (1H, s), 15.07 (1H, brs).

MS: m/z=391 [M+H]⁺.

Reference Example 20

According to Reference example 12, compound 20 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.26 (1H, m), 4.24 (1H, m), 4.27 (1H, d, J=12.0 Hz),4.41 (1H, d, J=14.8 Hz), 4.87 (1H, d, J=14.9 Hz), 5.75 (1H, d, J=7.6Hz), 7.09-7.77 (12H, m), 7.93 (1H, s), 8.52 (2H, m), 12.79 (1H, s),15.07 (1H, brs).

MS: m/z=482 [M+H]⁺.

Reference Example 21

According to Reference example 12, compound 21 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 0.62 (3H, d, J=6.9 Hz), 0.82 (3H, d, J=6.6 Hz), 3.18(1H, m), 3.75 (1H, d, J=10.2 Hz), 4.25 (1H, d, J=11.8 Hz), 4.58 (1H, m),5.65 (1H, d, J=11.3 Hz), 6.89-7.43 (10H, m), 7.67 (1H, s), 12.94 (1H,s).

MS: m/z=433 [M+H]⁺.

Reference Example 22

According to Reference example 12, compound 22 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.07-1.70 (5H, m), 3.04-3.34 (5H, m), 3.82 (2H, dm),4.18 (1H, d, J=10.2 Hz), 4.42 (1H, d, J=12.0 Hz), 5.81 (1H, d, J=11.7Hz), 7.11-7.59 (10H, m), 7.86 (1H, s), 12.96 (1H, s), 15.07 (1H, brs).

MS: m/z=489 [M+H]⁺.

Reference Example 23

According to Reference example 12, compound 23 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 0.01-0.79 (5H, m), 3.05 (1H, dd, J=14.1, 7.5 Hz),3.49-3.59 (2H, m), 4.16 (1H, dd, J=14.0, 3.3 Hz), 4.50 (1H, d, J=11.9Hz), 5.82 (1H, d, J=11.1 Hz), 7.11-7.62 (10H, m), 7.89 (1H, s), 12.99(1H, s), 15.07 (1H, brs).

MS: m/z=445 [M+H]⁺.

Reference Example 24

According to Reference example 12, compound 24 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.23 (1H, d, J=13.7 Hz), 4.16 (1H, dd, J=13.2, 3.3Hz), 4.19 (2H, d, J=12.0 Hz), 4.38 (1H, d, J=14.6 Hz), 4.84 (1H, d,J=14.6 Hz), 5.72 (1H, d, J=11.4 Hz), 7.08-7.33 (15H, m), 7.98 (1H, s),12.88 (1H, s), 15.07 (1H, s).

MS: m/z=481 [M+H]⁺.

Reference Example 25

According to Reference example 12, compound 25 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 3.37 (1H, m), 4.21 (1H, dd, J=14.4,3.9 Hz), 4.40 (1H, dd, J=11.7 Hz), 4.45 (1H, d, J=15.3 Hz), 4.81 (1H, d,J=15.4 Hz), 5.78 (1H, d, J=12.0 Hz), 6.30 (1H, s), 7.09-7.42 (10H, m),7.95 (1H, s), 12.65 (1H, s), 15.07 (1H, s).

MS: m/z=486 [M+H]⁺.

Reference Example 26

According to Reference example 12, compound 26 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.20-1.77 (6H, m), 3.11-3.61 (6H, m), 4.21 (1H, d,J=9.9 Hz), 4.53 (1H, d, J=11.7 Hz), 5.80 (1H, d, J=11.8 Hz), 7.14-7.65(10H, m), 7.95 (1H, s), 12.95 (1H, brs), 15.06 (1H, brs).

MS: m/z=489 [M+H]⁺.

Reference Example 27

According to Reference example 12, compound 27 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.36 (1H, m), 4.28 (1H, d, J=12.0 Hz), 4.54 (1H, d,J=11.4 Hz), 4.62 (1H, d, J=15.3 Hz), 4.79 (1H, d, J=15.4 Hz), 5.77 (1H,d, J=9.9 Hz), 7.09-7.79 (13H, m), 7.98 (1H, s), 8.46 (1H, d, J=4.6 Hz),12.82 (1H, brs), 15.06 (1H, brs).

MS: m/z=482 [M+H]⁺.

Reference Example 28

First Step

Compound 28A (3.20 g, 17.1 mmol) was added to THF (20 ml), triethylamine(2.60 ml, 18.8 mmol) was added, and the mixture was stirred at roomtemperature for 10 minutes. After Boc2O (4.09 g, 18.8 mmol) was added atroom temperature, the mixture was stirred for 2 hours. The solvent wasdistilled off under reduced pressure, water was added, and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous saturated sodium chloride solution, and dried with sodiumsulfate. The solvent was distilled off under reduced pressure to obtain5.17 g of compound 28B as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 2.77 (2H, m), 3.03-3.12 (1H, m), 3.38(1H, m), 3.90-3.98 (1H, m), 4.93 (1H, brs), 7.20-7.35 (5H, m).

Second Step

Compound 28B (4.29 g, 17.1 mmol), triphenylphosphine (5.37 g, 20.5 mmol)and phthalimide (2.76 g, 18.8 mmol) were added to THF (60 ml), anddiethyl azodicarboxylate (2.2M in toluene, 11.6 ml, 25.6 mmol) was addeddropwise at room temperature. After the mixture was stirred at roomtemperature for 1 hour, the solvent was distilled off under reducedpressure. The resulting crude product was purified by silica gel columnchromatography (n-hexane-ethyl acetate, 2:1, v/v) to obtain 6.13 g ofcompound 28C as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 3.14 (1H, dd, J=13.8, 6.2 Hz), 3.39 (2H,m), 3.87 (1H, m), 4.67 (1H, m), 4.81 (1H, brs), 7.16-7.19 (5H, m), 7.66(2H, dd, J=5.3, 3.1 Hz), 7.75 (2H, dd, J=5.7, 3.0 Hz).

Third Step

Compound 28C (1.00 g, 2.63 mmol) was added to THF (7 ml) and methanol (7ml), hydrazine hydrate (2.63 g, 52.6 mmol) was added, and the mixturewas stirred at 50° C. for 2 hours. The white precipitate was removed byfiltration, and washed with methanol. After the filtrate was distilledoff under reduced pressure, the resulting crude product was purified byamino column chromatography (chloroform-methanol, 99:1, v/v) to obtain249 mg of compound 28D as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.95 (2H, brs), 2.55-3.31 (5H, m), 5.06(H, brs), 7.18-7.33 (5H, m).

Fourth Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (313 mg, 0.983mmol) and 28D (246 mg, 0.983 mmol) were added to toluene (3 ml), and themixture was stirred at 100° C. for 2.5 hours. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol, 98:2,v/v) to obtain 320 mg of compound 28E as a pale yellow gummy substance.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 3.07 (2H, m), 3.56 (2H, m), 3.68 (3H,s), 3.95 (3H, s), 4.26 (1H, s), 4.86 (1H, s), 5.18 (1H, d, J=10.8 Hz),5.22 (1H, d, J=10.8 Hz), 7.01 (2H, m), 7.24-7.38 (8H, m), 8.22 (1H, s).

MS: m/z=551 [M+H]⁺.

Fifth Step

To compound 28E (315 mg, 0.572 mmol) was added 4N HCl (ethyl acetatesolution, 5 ml), and the mixture was stirred at room temperature for 30minutes. After the solvent was distilled off under reduced pressure,aqueous sodium bicarbonate water was added, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 95:5, v/v) to obtain 210 mg of compound 28F as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.07-3.15 (2H, m), 3.34 (1H, dd, J=13.2, 6.0 Hz), 3.74(2H, m), 3.86 (3H, s), 4.12 (1H, m), 5.27 (1H, d, J=10.1 Hz), 5.47 (1H,d, J=10.1 Hz), 6.76 (1H, d, J=6.4 Hz), 7.04 (2H, m), 7.32 (6H, m), 7.62(2H, dd, J=7.7, 1.4 Hz), 7.70 (1H, s).

MS: m/z=419 [M+H]⁺.

Sixth Step

Compound 28F (50 mg, 0.12 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (195 mg, 0.597 mmol) was added. After the mixture was stirredat room temperature for 30 minutes, iodoethane (0.048 ml, 0.60 mmol) wasadded, and the mixture was stirred at room temperature for 3.5 hours.The reaction solution was poured into water, and the mixture wasextracted with ethyl acetate, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 95:5, v/v) to obtain 47 mg of compound 28G as acolorless solid.

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.2 Hz), 3.00-3.15 (2H, m), 3.28 (1H,dd, J=13.6, 1.6 Hz), 3.48 (1H, m), 3.75 (1H, m), 3.85 (3H, s), 3.88 (1H,dd, J=13.3, 3.2 Hz), 4.15 (1H, m), 5.25 (1H, d, J=9.9 Hz), 5.50 (1H, d,J=9.9 Hz), 7.04 (2H, m), 7.29-7.38 (6H, m), 7.60 (1H, s), 7.68 (2H, m).

MS: m/z=447 [M+H]⁺.

Seventh Step

Compound 28G (47 mg, 0.11 mmol) was dissolved in THF (0.5 ml) andmethanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.26 ml, 0.53mmol) was added at room temperature, and the mixture was stirred for 1hour. After 1N hydrochloric acid was added, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, 40 mg ofcompound 28H was obtained as a colorless solid.

MS: m/z=433 [M+H]⁺.

Eighth Step

To compound 28H obtained in the seventh step was added trifluoroaceteicacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 3 withsodium bicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 17 mg of compound 28 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=7.2 Hz), 3.08 (2H, m), 3.51-3.63 (3H,m), 4.08 (1H, dd, J=13.6, 3.9 Hz), 5.03 (1H, brs), 7.21 (5H, m), 8.07(1H, s), 12.98 (1H, s), 15.07 (1H, brs).

MS: m/z=343 [M+H]⁺.

Reference Example 29

According to Reference example 28, compound 29 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.96 (2H, d, J=7.6 Hz), 3.46 (1H, d, J=13.3 Hz),4.06 (1H, dd, J=13.6, 3.8 Hz), 4.64 (1H, d, J=14.9 Hz), 4.89 (1H, d,J=14.6 Hz), 4.98 (1H, m), 6.97 (2H, m), 7.10-7.37 (5H, m), 7.57 (1H, m),8.12 (1H, s), 12.75 (1H, s), 15.07 (1H, brs).

Reference Example 30

According to Reference example 28, compound 30 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.99 (2H, dd, J=7.5, 3.6 Hz), 3.48 (1H, d, J=13.4Hz), 4.09 (1H, dd, J=13.4, 4.0 Hz), 4.73 (1H, d, J=15.1 Hz), 4.92 (1H,d, J=15.1 Hz), 4.99 (1H, m), 6.97 (2H, m), 7.18-7.29 (4H, m), 7.49 (1H,m), 7.61 (1H, m), 8.15 (1H, s), 12.69 (1H, s), 15.06 (1H, brs).

Reference Example 31

According to Reference example 28, compound 31 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.91 (2H, m), 3.45 (1H, d, J=13.1 Hz), 4.02 (1H, dd,J=13.6, 4.0 Hz), 4.57 (1H, d, J=14.6 Hz), 4.91 (1H, d, J=14.6 Hz), 4.93(1H, m), 6.89 (2H, m), 7.18 (3H, m), 7.40 (5H, m), 8.16 (1H, s), 12.86(1H, brs), 15.06 (1H, brs).

MS: m/z=405 [M+H]⁺.

Reference Example 32

According to Reference example 28, compound 32 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.10 (2H, m), 3.39 (1H, d, J=13.6 Hz), 3.84 (1H, dd,J=13.6, 4.0 Hz), 4.94 (1H, m), 7.23 (5H, m), 8.19 (1H, s), 9.44 (1H,brs), 12.97 (1H, s), 15.06 (1H, brs).

MS: m/z=315 [M+H]⁺.

Reference Example 33

According to Reference example 28, compound 33 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.09 (3H, t, J=6.9 Hz), 3.10 (2H, m), 3.42-3.50 (2H,m), 3.71 (5H, m), 4.11 (1H, dd, J=13.6, 3.8 Hz), 4.99 (1H, brs),7.11-7.29 (5H, m), 7.99 (1H, s), 12.88 (1H, s), 15.06 (1H, brs).

MS: m/z=387 [M+H]⁺.

Reference Example 34

According to Reference example 28, compound 34 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, d, J=6.9 Hz), 1.21 (3H, d, J=6.9 Hz), 2.98(1H, dd, J=13.6, 9.8 Hz), 3.13 (1H, dd, J=13.7, 5.8 Hz), 3.68 (1H, d,J=12.8 Hz), 3.87 (1H, dd, J=13.6, 3.7 Hz), 4.83 (1H, quin, J=6.8 Hz),5.07 (1H, brs), 7.19 (5H, m), 7.90 (1H, s), 13.09 (1H, s), 15.08 (1H,brs).

MS: m/z=357 [M+H]⁺.

Reference Example 35

According to Reference example 28, compound 35 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.07 (3H, s), 3.14 (2H, m), 3.49 (1H, d, J=13.3 Hz),4.08 (1H, dd, J=13.7, 4.0 Hz), 4.99 (1H, m), 7.13-7.31 (5H, m), 8.18(1H, s), 12.95 (1H, s), 15.06 (1H, brs).

MS: m/z=329 [M+H]⁺.

Reference Example 36

First Step

Compound 12H (460 mg, 0.930 mmol) was dissolved in THF (2.5 ml) andmethanol (2.5 ml), a 2N aqueous sodium hydroxide solution (2.33 ml, 4.65mmol) was added at room temperature, and the mixture was stirred for 1.5hours. After 1N hydrochloric acid was added, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, 405 mg ofcompound 36A was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.45 (1H, ddd, J=13.8, 6.9, 1.3 Hz), 3.80 (1H, dd,J=13.5, 2.1 Hz), 4.35 (1H, d, J=11.6 Hz), 4.77 (1H, d, J=11.3 Hz), 5.46(1H, d, J=10.5 Hz), 5.52 (1H, d, J=10.5 Hz), 6.11 (1H, d, J=5.8 Hz),6.94-6.98 (2H, m), 7.17 (3H, m), 7.31-7.46 (8H, m), 7.58 (3H, m).

Second Step

Compound 36A (402 mg, 0.837 mmol) was added to diphenyl ether (5 ml),and the mixture was stirred at 245° C. for 1 hour under microwaveirradiation. The reaction solution was poured into n-hexane, and theprecipitated solid was filtered. The resulting crude product waspurified by amino column chromatography (chloroform-methanol, 99:1, v/v)to obtain 164 mg of compound 36B as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.36 (1H, dd, J=13.0, 7.0 Hz), 3.72 (1H, d, J=11.1Hz), 4.35 (1H, d, J=11.4 Hz), 4.49 (1H, d, J=10.2 Hz), 5.38 (1H, d,J=10.5 Hz), 5.43 (1H, d, J=10.4 Hz), 5.94 (1H, d, J=7.2 Hz), 6.29 (1H,d, J=6.6 Hz), 6.38 (1H, d, J=7.5 Hz), 6.99 (2H, m), 7.17 (3H, m), 7.36(8H, m), 7.60 (2H, m).

Third Step

Compound 36B (40 mg, 0.092 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (179 mg, 0.55 mmol) was added. After stirring at roomtemperature for 30 minutes, iodomethane (0.029 ml, 0.46 mmol) was added,and the mixture was stirred at room temperature for 3.5 hours. Thereaction solution was poured into water, and the mixture was extractedwith ethyl acetate, and dried with sodium sulfate. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol, 95:5,v/v) to obtain 44 mg of compound 36C as a colorless gummy substance.

Fourth Step

To compound 36C obtained in the third step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,chloroform-ethyl ether were added, and the precipitated solid wasfiltered to obtain 24 mg of compound 36 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.93 (3H, s), 3.17 (1H, d, J=13.0 Hz), 4.13 (1H, dd,J=13.6, 3.4 Hz), 4.47 (1H, d, J=11.4 Hz), 5.52 (1H, dd, J=9.3, 3.4 Hz),5.99 (1H, d, J=7.3 Hz), 7.18 (4H, m), 7.30 (3H, m), 7.41 (2H, t, J=7.5Hz), 7.60 (2H, d, J=7.2 Hz).

MS: m/z=361 [M+H]⁺.

Reference Example 37

According to Reference example 36, compound 37 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.16 (2H, d, J=13.3 Hz), 4.05 (1H, d, J=10.5 Hz),4.15 (1H, d, J=11.7 Hz), 4.38 (1H, d, J=14.9 Hz), 4.74 (1H, d, J=14.5Hz), 5.35 (1H, d, J=11.4 Hz), 5.65 (1H, d, J=7.3 Hz), 6.99 (1H, d, J=7.5Hz), 7.21 (15H, m).

MS: m/z=437 [M+H]⁺.

Reference Example 38

According to Reference example 36, compound 38 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.57 (2H, m), 3.17 (3H, s), 3.21-3.31 (5H, m), 4.07(1H, dd, J=13.5, 3.7 Hz), 4.36 (1H, d, J=11.6 Hz), 5.42 (1H, d, J=9.2Hz), 5.61 (1H, d, J=7.3 Hz), 6.89 (1H, d, J=7.5 Hz), 7.13-7.31 (6H, m),7.40 (2H, t, J=6.3 Hz), 7.57 (2H, d, J=7.3 Hz), 12.31 (1H, brs).

MS: m/z=419 [M+H]⁺.

Reference Example 39

According to Reference example 36, compound 39 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.12 (1H, dd, J=13.6, 5.5 Hz), 3.87 (1H, d, J=9.5Hz), 4.44 (1H, d, J=11.7 Hz), 5.45 (1H, d, J=10.4 Hz), 5.83 (1H, d,J=7.5 Hz), 7.04 (1H, d, J=7.2 Hz), 7.14-7.31 (6H, m), 7.40 (2H, t, J=7.5Hz), 7.58 (2H, d, J=7.5 Hz), 9.09 (1H, d, J=5.2 Hz).

MS: m/z=347 [M+H]⁺.

Reference Example 40

According to Reference example 36, compound 40 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.88-3.15 (2H, m), 3.27 (3H, s), 3.53-3.73 (5H, m),3.99 (1H, dd, J=13.27, 3.97 Hz), 4.56-4.60 (1H, m), 5.89 (1H, d, J=7.32Hz), 7.08-7.30 (6H, m).

Reference Example 41

First Step

Compound 41A (290 mg, 0.555 mmol) synthesized according to Referenceexample 12 was added to diphenyl ether (5 ml), and the mixture wasstirred at 245° C. for 1 hour under microwave irradiation. The reactionsolution was poured into n-hexane, and the precipitated solid wasfiltered. The resulting crude product was purified by amino columnchromatography (chloroform-methanol, 99:1→97:3, v/v) to obtain 86 mg ofcompound 41B as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.9 Hz),3.43-3.52 (2H, m), 3.62 (1H, dd, J=13.6, 3.5 Hz), 4.22 (1H, d, J=11.6Hz), 4.52 (1H, d, J=11.6 Hz), 4.86-4.95 (1H, m), 5.37 (1H, d, J=10.2Hz), 5.45 (1H, d, J=10.2 Hz), 5.90 (1H, d, J=7.5 Hz), 6.22 (1H, d, J=7.5Hz), 6.89 (2H, m), 7.15 (3H, m), 7.36 (8H, m), 7.67 (2H, m).

Second Step

To compound 41B obtained in the first step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 45 mg of compound 41 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 0.82 (3H, d, J=6.7 Hz), 1.05 (3H, d, J=6.7 Hz), 3.90(1H, dd, J=13.6, 3.4 Hz), 4.39 (1H, d, J=11.9 Hz), 4.77-4.86 (1H, m),5.50 (1H, d, J=8.6 Hz), 5.69 (1H, d, J=7.4 Hz), 6.92 (1H, d, J=7.4 Hz),7.15-7.48 (8H, m), 7.63 (2H, d, J=7.7 Hz) 12.51 (1H, Brs).

MS: m/z=389 [M+H]⁺.

Reference Example 42

According to Reference example 41, compound 42 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.12 (3H, s), 3.51 (5H, m), 4.05 (1H, dd, J=13.9,3.5 Hz), 4.37 (1H, d, J=11.4 Hz), 5.38 (1H, d, J=11.6 Hz), 5.60 (1H, d,J=7.3 Hz), 6.90 (1H, d, J=7.5 Hz), 7.22 (6H, m), 7.40 (2H, t, J=7.5 Hz),7.56 (2H, d, J=7.2 Hz).

MS: m/z=405 [M+H]⁺.

Reference Example 43

First Step

Compound 43A (2.00 g, 6.11 mmol), triphenylphosphine (2.40 g, 9.16 mmol)and phthalimide (1.08 g, 7.33 mmol) were added to THF (20 ml), anddiethyl azodicarboxylate (2.2M in toluene, 4.16 ml, 9.16 mmol) was addeddropwise at room temperature. After stirring at room temperature for 3hours, the solvent was distilled off under reduced pressure. Theresulting crude product was purified by silica gel column chromatography(n-hexane-ethyl acetate, 1:1, v/v) to obtain 2.39 g of compound 43B as acolorless solid.

¹H-NMR (DMSO-d₆) δ: 1.00 (9H, s), 3.30 (1H, m), 3.61 (1H, dd, J=13.4,10.2 Hz), 4.15 (1H, d, J=12.2 Hz), 4.75 (1H, m), 6.79 (1H, d, J=9.5 Hz),7.25 (15H, m), 7.76-7.89 (4H, m).

Second Step

Compound 43B (2.06 g, 4.51 mmol) was added to THF (20 ml) and methanol(20 ml), hydrazine hydrate (4.52 g, 90.2 mmol) was added, and themixture was stirred at 60° C. for 5 hours. The white precipitate wasremoved by filtration, and washed with methanol. After the filtrate wasdistilled off under reduced pressure, the resulting crude product waspurified by amino column chromatography (chloroform-methanol, 99:1,v/v), n-hexane was added, and the precipitated solid was filtered toobtain 1.25 g of compound 43C as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.32 (9H, s), 2.55 (1H, dd, J=13.3, 6.0 Hz), 2.80 (1H,dd, J=13.3, 3.5 Hz), 3.99 (1H, d, J=10.1 Hz), 4.47 (2H, m), 7.13-7.33(10H, m).

Third Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (488 mg, 1.53mmol) and 43C (500 mg, 1.53 mmol) were added to toluene (8 ml), and themixture was stirred at 110° C. for 1 hour. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,97:3→96:4→94:6, v/v) to obtain 667 mg of compound 43D as a pale yellowgummy substance.

¹H-NMR (CDCl₃) δ: 1.28 (9H, s), 3.63 (3H, s), 3.80 (1H, m), 3.87 (3H,s), 4.02 (1H, dd, J=14.5, 10.1 Hz), 4.21 (1H, d, J=10.4 Hz), 4.47 (2H,m), 5.20 (1H, d, J=10.8 Hz), 5.26 (1H, d, J=10.7 Hz), 7.30 (15H, m),8.05 (1H, s).

MS: m/z=627 [M+H]⁺.

Fourth Step

To compound 43D (664 mg, 1.06 mmol) was added 4N HCl (ethyl acetatesolution, 10 ml), and the mixture was stirred at room temperature for 1hour. After the solvent was distilled off under reduced pressure, THFand saturated sodium bicarbonate water were added, and the mixture wasstirred for 2.5 hours. This was extracted with chloroform, and driedwith sodium sulfate. After the solvent was distilled off under reducedpressure, methylene chloride-ethyl ether were added, and theprecipitated solid was filtered to obtain 458 mg of compound 43E as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.86 (3H, m), 3.92 (3H, s), 4.41-4.48 (1H, m), 5.32(1H, d, J=10.8 Hz), 5.42 (1H, d, J=10.1 Hz), 5.92 (1H, s), 7.21-7.39(13H, m), 7.59 (2H, m), 7.89 (1H, s).

MS: m/z=495 [M+H]⁺.

Fifth Step

Compound 43E (50 mg, 0.10 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (165 mg, 0.51 mmol) was added. After the mixture was stirredat room temperature for 30 minutes, iodomethane (0.025 ml, 0.40 mmol)was added, and the mixture was stirred at room temperature for 1 hour.The reaction solution was poured into water, and the mixture wasextracted with ethyl acetate, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 97:3→95:5, v/v) to obtain 60 mg of compound 43F asa colorless solid.

¹H-NMR (CDCl₃) δ: 2.57 (3H, s), 3.75 (2H, d, J=11.3 Hz), 3.93 (3H, s),4.20-4.29 (2H, m), 5.25 (1H, d, J=9.9 Hz), 5.57 (1H, d, J=9.9 Hz),7.15-7.41 (13H, m), 7.63 (1H, s), 7.72-7.76 (2H, m).

Sixth Step

Compound 43F obtained in the fifth step was dissolved in THF (0.5 ml)and methanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.25 ml,0.50 mmol) was added at room temperature, and the mixture was stirredfor 1 hour. After 1N hydrochloric acid was added, and the mixture wasextracted with ethyl acetate, the extract was dried with sodium sulfate.After the solvent was distilled off under reduced pressure, a colorlessgummy compound 43G was obtained.

Seventh Step

To compound 43G obtained in the sixth step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 3 withsodium bicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, chloroform-ethyl etherwere added, and the precipitated solid was filtered to obtain 27 mg ofcompound 43 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 4.26 (1H, d, J=10.9 Hz), 4.35 (1H, d,J=13.3 Hz), 4.58 (1H, dd, J=13.8, 3.5 Hz), 5.06 (1H, d, J=10.9 Hz), 7.36(10H, m), 8.36 (1H, s), 12.58 (1H, s), 15.62 (1H, s).

MS: m/z=405 [M+H]⁺.

Reference Example 44

According to Reference example 43, compound 44 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 4.19 (2H, m), 4.42 (1H, dd, J=13.3, 3.8 Hz), 4.90(1H, d, J=9.2 Hz), 7.17-7.41 (10H, m), 8.40 (1H, s), 9.66 (1H, s), 12.70(1H, s), 15.60 (1H, s).

MS: m/z=391 [M+H]⁺.

Reference Example 45

According to Reference example 43, compound 45 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.17-2.26 (1H, m), 3.22 (3H, s), 3.39 (2H, m),3.58-3.67 (1H, m), 4.19 (1H, d, J=10.7 Hz), 4.38 (2H, m), 4.95 (1H, d,J=10.8 Hz), 7.20-7.44 (10H, m), 8.28 (1H, s), 12.40 (1H, s), 15.60 (1H,s).

MS: m/z=449 [M+H]⁺.

Reference Example 46

First Step

Compound 43E (289 mg, 0.584 mmol) obtained in Reference example 35 wasdissolved in THF (3 ml) and methanol (3 ml), a 2N aqueous sodiumhydroxide solution (1.46 ml, 2.92 mmol) was added at room temperature,and the mixture was stirred for 1.5 hours. After 1N hydrochloric acidwas added, and the mixture was extracted with ethyl acetate, the extractwas dried with sodium sulfate. After the solvent was distilled off underreduced pressure, 342 mg of compound 46A was obtained as a colorlesssolid.

¹H-NMR (CDCl₃) δ: 3.72-4.04 (3H, m), 4.46 (1H, m), 5.39 (1H, d, J=10.4Hz), 5.44 (1H, d, J=10.4 Hz), 6.04 (1H, brs), 7.19-7.60 (15H, m), 8.10(1H, s).

Second Step

Compound 46A (402 mg, 0.837 mmol) was added to diphenyl ether (5 ml),and the mixture was stirred at 245° C. for 1 hour under microwaveirradiation. The reaction solution was poured into n-hexane, and theprecipitated solid was filtered. The resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,97:3→95:5→92:8, v/v) to obtain 85 mg of compound 46B as a colorlesssolid.

¹H-NMR (CDCl₃) δ: 3.86 (3H, m), 4.45 (1H, m), 5.35 (1H, d, J=10.5 Hz),5.41 (1H, d, J=10.4 Hz), 5.94 (1H, brs), 6.48 (1H, d, J=7.4 Hz), 7.00(1H, d, J=7.4 Hz), 7.25-7.44 (13H, m), 7.62 (2H, m).

Third Step

Compound 46B (39 mg, 0.089 mmol) was dissolved in DMF (1 ml), and cesiumcarbonate (145 mg, 0.445 mmol) was added. After stirring at roomtemperature for 30 minutes, 1-bromo-2-methoxyethane (0.033 ml, 0.36mmol) was added, and the mixture was stirred at room temperature for 3.5hours. The reaction solution was poured into water, and the mixture wasextracted with ethyl acetate, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 97:3→95:5→92:8, v/v) to obtain 66 mg of compound46C as a colorless gummy substance.

Fourth Step

To compound 46C obtained in the third step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 21 mg of compound 46 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.12-2.21 (1H, m), 3.20 (3H, s), 3.55-3.64 (3H, m),3.81 (1H, d, J=13.0 Hz), 3.99 (1H, d, J=11.0 Hz), 4.22 (1H, dd, J=13.3,3.1 Hz), 4.86 (1H, d, J=11.0 Hz), 6.11 (1H, d, J=7.2 Hz), 7.18-7.45(11H, m).

MS: m/z=405 [M+H]⁺.

Reference Example 47

According to Reference example 46, compound 47 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.70 (1H, d, J=12.2 Hz), 4.02 (1H, d, J=10.7 Hz),4.17 (1H, dd, J=13.2, 3.6 Hz), 4.79 (1H, t, J=3.4 Hz), 6.11 (1H, d,J=7.3 Hz), 7.18-7.44 (11H, m), 9.23 (1H, d, J=4.3 Hz).

MS: m/z=347 [M+H]⁺.

Reference Example 48

First Step

Compound 41A (400 mg, 0.743 mmol) was dissolved in DMF (5 ml),triethylamine (0.21 ml, 1.5 mmol) and ethyl chloroformate (0.143 ml,1.49 mmol) were added at 0° C., and the mixture was stirred for 20minutes. Sodium borohydride (70.2 mg, 1.86 mmol) was added at 0° C., andthe mixture was stirred at room temperature for 30 minutes. Sodiumborohydride (70.2 mg, 1.86 mmol) was further added at 0° C., and themixture was stirred at room temperature for 2 hours. The reactionsolution was poured into water, the mixture was extracted with ethylacetate, and the extract was dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 97:3, v/v) to obtain 160 mg of compound 48A as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.19 (3H, s), 3.37-3.54 (3H, m), 3.65-3.73 (1H, m),3.87 (1H, m), 4.06 (2H, d, J=13.9 Hz), 4.31 (1H, d, J=11.2 Hz), 4.39(1H, d, J=13.8 Hz), 4.77 (1H, d, J=11.2 Hz), 5.36 (1H, d, J=10.1 Hz),5.41 (1H, d, J=10.1 Hz), 6.65 (1H, brs), 7.00 (2H, m), 7.19 (3H, m),7.33-7.49 (8H, m), 7.70 (2H, m).

Second Step

To compound 48A (50 mg, 0.095 mmol) was added trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 6 with sodiumbicarbonate water and 2N hydrochloric acid, the mixture was extractedwith chloroform, and the extract was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, chroloform-ethyl etherwere added, and the precipitated solid was filtered to obtain 3.5 mg ofcompound 48 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 3.12 (3H, s), 3.51 (5H, m), 3.71 (1H, d, J=13.7 Hz),4.02 (1H, d, J=9.9 Hz), 4.09 (1H, d, J=12.0 Hz), 4.36 (1H, d, J=11.6Hz), 4.73 (1H, brs), 5.45 (1H, d, J=12.5 Hz), 7.00 (1H, s), 7.15 (5H,m), 7.28 (1H, t, J=7.2 Hz), 7.40 (2H, t, J=7.5 Hz), 7.59 (2H, d, J=7.6Hz).

MS: m/z=435 [M+H]⁺.

Reference Example 49

First Step

To Dess-Martin Periodinane (0.3M, methylene chrolide solution, 52.0 ml,15.6 mmol) was added dropwise a methylene chloride solution (20 ml) ofcompound 49A (2.97 g, 10.4 mmol) at 0° C. After stirring at roomtemperature for 3 hours, the reaction mixture was poured into a 1Naqueous sodium hydroxide solution, and the mixture was extracted withethyl ether. The organic layer was washed with a 1N aqueous sodiumhydroxide solution and an aqueous saturated sodium chloride solution,and dried with magnesium sulfate. After the solvent was distilled offunder reduced pressure, 2.08 g of compound 49B was obtained as a whitesolid.

¹H-NMR (CDCl₃) δ: 3.13 (2H, d, J=6.6 Hz), 4.53 (1H, q, J=6.7 Hz), 5.12(2H, s), 5.28 (1H, brs), 7.26 (10H, m), 9.64 (1H, s).

Second Step

Compound 49B (700 mg, 2.47 mmol), 2-aminoethanol (166 mg, 2.72 mmol) andsodium sulfate (1.76 g, 12.4 mmol) were added to toluene (20 ml), andthe mixture was stirred at room temperature for 1 hour. Boc2O (0.631 ml,2.72 mmol) was added at room temperature, and the mixture was stirredfor 18 hours. The reaction solution was filtered, and the filtrate wasconcentrated under reduced pressure. The resulting crude product waspurified by silica gel column chromatography (n-hexane-ethyl acetate,1:1, v/v) to obtain 893 mg of 49C as a colorless gummy substance.

Third Step

Compound 49C (890 mg, 2.09 mmol) and palladium-active carbon (10%, wet,200 mg) were added to ethanol (20 ml), and the mixture was stirred atroom temperature for 2 hours under hydrogen atmosphere. After filtrationwith celite, the solvent was concentrated under reduced pressure toobtain 656 mg of a colorless oily substance 49D.

¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 2.65-2.86 (2H, m), 3.32 (2H, m), 3.80(2H, m), 4.03-4.12 (1H, m), 4.86 (1H, brs), 7.22 (5H, m).

Fourth Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (610 mg, 2.09mmol) and 49D (664 mg, 2.09 mmol) were added to toluene (6 ml), and themixture was stirred at 100° C. for 4 hours. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (n-hexane-ethyl acetate,1:1, v/v) to obtain 884 mg of compound 49E as a pale yellow gummysubstance.

MS: m/z=593 [M+H]⁺.

Fifth Step

To compound 49E (860 mg, 1.45 mmol) was added 4N HCl (ethyl acetatesolution, 10 ml). After stirring at room temperature for 30 minutes, thesolvent was distilled off under reduced pressure. Subsequently, toluene(10 ml) and 2-aminoethanol (0.175 ml, 2.90 mmol) were added, and themixture was stirred at 80° C. for 30 minutes. After the solvent wasdistilled off under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,99:1→95:5→90:10, v/v) to obtain 157 mg of compound 49F as a colorlessgummy substance and 217 mg of compound 49G as a yellow solid.

49F: ¹H-NMR (CDCl₃) δ: 2.48 (1H, dd, J=14.0, 11.4 Hz), 3.22 (1H, dd,J=14.1, 3.3 Hz), 3.69 (1H, m), 3.77 (3H, s), 3.83-3.95 (1H, m), 4.08(1H, m), 4.29 (1H, m), 4.41 (1H, m), 5.34 (2H, m), 5.48 (1H, d, J=10.1Hz), 6.86 (2H, m), 7.20-7.39 (7H, m), 7.64 (2H, m)

49G: ¹H-NMR (DMSO-d₆) δ: 3.70 (2H, t, J=5.3 Hz), 3.73 (3H, s), 3.86 (2H,t, J=5.3 Hz), 4.14 (2H, s), 4.98 (1H, t, J=5.0 Hz), 5.06 (2H, s), 6.98(1H, s), 7.35 (8H, m), 7.62 (2H, d, J=7.1 Hz), 8.34 (1H, d, J=0.8 Hz).

Sixth Step

The compound 49G (214 mg, 0.465 mmol) was dissolved in THF (4 ml),ethanol (2 ml) and methylene chloride (2 ml), a 2N aqueous sodiumhydroxide solution (1.16 ml, 2.32 mmol) was added at room temperature,and the mixture was stirred for 2.5 hours. After 1N hydrochloric acidwas added, and the mixture was extracted with chloroform, the extractwas dried with sodium sulfate. After the solvent was distilled off underreduced pressure, 158 mg of compound 49H was obtained as a yellow solid.

¹H-NMR (DMSO-d₆) δ: 3.70 (2H, q, J=5.2 Hz), 3.89 (2H, t, J=5.3 Hz), 4.22(2H, s), 4.97 (1H, t, J=5.6 Hz), 5.12 (2H, s), 7.23-7.41 (9H, m), 7.60(2H, m), 8.54 (1H, s).

Seventh Step

Compound 49H (50.0 mg, 0.112 mmol) and palladium-active carbon (10%,wet, 12 mg) were added to methanol (1 ml) and DMF (3 ml), and themixture was stirred at room temperature for 5 hours under hydrogenatmosphere. After filtration with celite, the solvent was concentratedunder reduced pressure, chloroform-methanol-ethyl ether were added, andthe precipitated solid was filtered to obtain 9.0 mg of compound 49 as acolorless solid.

¹H-NMR (DMSO-d₆) δ: 3.10 (2H, m), 3.51-3.69 (4H, m), 4.10 (1H, d, J=10.7Hz), 4.94 (2H, m), 7.11-7.26 (5H, m), 8.03 (1H, s), 12.94 (1H, brs),15.30 (1H, brs).

MS: m/z=359 [M+H]⁺.

Reference Example 50

First Step

Compound 50A (1.00 g, 3.98 mmol), triphenylphosphine (1.15 g, 4.48 mmol)and N-methyl-2-nitrobenzenesulfonamide (860 mg, 3.98 mmol) were added toTHF (10 ml), and diethyl azodicarboxylate (2.2M in toluene, 1.99 ml,4.38 mmol) was added dropwise at room temperature. After stirring atroom temperature for 3 hours, the solvent was distilled off underreduced pressure. The resulting crude product was purified by silica gelcolumn chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 710mg of compound 50B as a colorless gummy substance.

Second Step

Compound 50B (458 mg, 1.02 mmol) was dissolved in acetonitrile,potassium carbonate (422 mg, 3.06 mmol) and benzenethiol (0.126 ml, 1.22mmol) were added, and the mixture was stirred at room temperature for 5hours. The reaction solution was poured into a 1N aqueous sodiumhydroxide solution, the mixture was extracted with methylene chloride,and the extract was dried with sodium sulfate. The resulting crudeproduct was purified by amino column chromatography(chloroform-methanol, 95:5, v/v) to obtain 147 mg of compound 50C as acolorless oily substance.

¹H-NMR (CDCl₃) δ: 1.36 (9H, s), 2.40 (3H, s), 2.51-2.89 (4H, m), 3.90(1H, s), 4.69 (1H, s), 7.17-7.31 (5H, m).

Third Step

Compound 50C (140 mg, 0.530 mmol) and3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (WO 2006/116764, 119 mg,0.482 mmol) were added to THF (3 ml),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg,0.578 mmol) and 1-hydroxybenzotriazole (65.1 mg, 0.482 mmol) were added,and the mixture was stirred at room temperature for 18 hours. Thereaction solution was poured into sodium bicarbonate water, the mixturewas extracted with ethyl acetate, and the extract was dried with sodiumsulfate. The resulting crude product was purified by silica gel columnchromatography (chloroform-methanol, 97:3, v/v) to obtain 219 mg ofcompound 50D as a colorless solid.

MS: m/z=493 [M+H]⁺.

Fourth Step

To compound 50D (216 mg, 0.439 mmol) was added 4N HCl (ethyl acetatesolution, 3 ml). After the mixture was stirred at room temperature for 1hour, the solvent was distilled off under reduced pressure.Subsequently, ethanol (4 ml) and an aqueous saturated sodium carbonatesolution (3 ml) were added, and the mixture was stirred at 60° C. for 2hours. After water was added, and the mixture was extracted with ethylacetate, the extract was dried with sodium sulfate. The resulting crudeproduct was purified by amino column chromatography(chloroform-methanol, 95:5, v/v) to obtain 108 mg of compound 50E as apale yellow gummy substance.

¹H-NMR (CDCl₃) δ: 3.00 (2H, m), 3.13 (3H, s), 3.18 (1H, m), 3.88 (1H,dd, J=13.5, 3.4 Hz), 4.00-4.07 (1H, m), 5.26 (1H, d, J=10.2 Hz), 5.46(1H, d, J=10.1 Hz), 6.25 (1H, d, J=7.5 Hz), 6.73 (1H, d, J=7.5 Hz),6.99-7.02 (2H, m), 7.28-7.37 (6H, m), 7.63-7.67 (2H, m).

Fifth Step

To compound 50E (105 mg, 0.280 mmol) was added trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 30 minutes.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-methanol-ethyl ether were added, and the precipitatedsolid was filtered to obtain 29 mg of compound 50 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.99 (3H, s), 3.26-3.47 (3H, m), 4.07 (1H, d, J=11.1Hz), 4.80 (1H, m), 6.43 (1H, d, J=6.9 Hz), 7.11-7.29 (5H, m), 7.50 (1H,d, J=6.9 Hz).

MS: m/z=285[M+H]⁺.

Reference Example 51

First Step

Compound 1D (60 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Thereaction solution was distilled off, and the resulting residue waspurified by LC/MS to obtain compound 51 (43 mg, 0.09 mmol).

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=6.9 Hz), 3.11 (3H, s), 3.48-3.58 (2H,m), 3.95-4.12 (3H, m), 4.40 (1H, d, J=11.4 Hz), 5.59 (1H, d, J=11.4 Hz),7.11 (1H, d, J=7.3 Hz), 7.17 (2H, t, J=7.2 Hz), 7.26 (2H, d, J=7.1 Hz),7.30 (1H, t, J=7.3 Hz), 7.42 (2H, t, J=7.2 Hz), 7.60 (3H, m), 12.55 (1H,brs).

MS: m/z=477.2 [M+H]⁺.

Reference Example 52

First Step

To a DMF (10 ml) solution of compound 1I (2.0 g, 4.32 mmol) were addedWSC HCl (1.24 g, 6.49 mmol) and HOBt (876.9 mg, 6.49 mmol) at roomtemperature, and the mixture was stirred at the same temperature for 1hour. To the reaction solution were added O,N-dimethylhydroxylaminehydrochloride (842.7 mg, 8.64 mmol) and triethylamine (2.19 g, 21.6mmol), the mixture was stirred at the same temperature for 3 hours,thereafter, water was added, and the mixture was extracted with ethylacetate three times. After the extract was washed with water threetimes, and dried with sodium sulfate, the solvent was distilled off, andthe resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with n-hexane-ethyl acetate (7:3, v/v)and, then, with only ethyl acetate. Concentration of an objectivefraction afforded 543 mg (yield 25%) of compound 52A as an oil.

MS: m/z=506 [M+H]⁺.

Second Step

A THF (5 ml) solution of compound 52A (543 mg, 1.07 mmol) was cooled to−78° C., a methylmagnesium bromide 0.97M THF solution (1.66 ml, 1.61mmol) was added, and temperature was raised up to −20° C. over 2 hours.To the reaction solution was added 1N hydrochloric acid, and the mixturewas extracted with ethyl acetate three times. After the extract wasdried with sodium sulfate, the solvent was distilled off, and theresulting oil was purified by silica gel chromatography. The materialswere eluted firstly with n-hexane-ethyl acetate (7:3, v/v) and, then,with only ethyl acetate. Concentration of an objective fraction afforded256.8 mg (yield 52%) of compound 52B as an oil.

¹H-NMR (CDCl₃) δ: 2.65 (3H, s), 3.08 (2H, d, J=7.5 Hz), 3.12 (3H, s),3.53-3.68 (4H, m), 3.79-3.95 (1H, m), 3.92 (1H, dd, J=3.3 Hz, 13.5 Hz),4.10-4.16 (1H, m), 5.30 (1H, d, J=10.2 hz), 5.45 (1H, d, J=10.2 Hz),6.99-7.02 (2H, m), 7.25-7.38 (6H, m), 7.49 (1H, s), 7.63-7.66 (2H, m).

Third Step

To a dichloromethane (4 ml) solution of compound 52B (256 mg, 0.558mmol) was added mCPBA (144.3 mg, 0.836 mmol) under ice-cooling, and themixture was stirred at room temperature for 2 hours. To the reactionsolution was added an aqueous sodium thiosulfate solution, and themixture was extracted with ethyl acetate three times. After the extractwas washed with saturated sodium bicarbonate water two times, and driedwith sodium sulfate, the solvent was distilled off, the resulting oilwas dissolved in ethanol (4 ml), and a 2N-aqueous sodium hydroxidesolution (1 ml) was added, followed by refluxing for 1 hour. After thesolvent was distilled off, the precipitated solid was washed withdiisopropyl ether to obtain 242 mg (yield 100%) of compound 52C.

¹H-NMR (CDCl₃) δ: 3.09 (2H, d, J=6.9 Hz), 3.32 (3H, s), 3.54 (1H, d,J=14.1 Hz), 3.59-3.71 (2H, m), 3.76-3.85 (1H, m), 3.92 (1H, dd, J=3.6Hz, 13.5 Hz), 4.03 (1H, brt), 5.28 (1H, d, J=10.2 Hz), 5.47 (1H, d,J=10.2 Hz), 6.68 (1H, s), 7.00-7.04 (2H, m), 7.23-7.37 (6H, m), 7.64(2H, d, J=6.3 Hz).

Fourth Step

To a THF (3 ml) solution of compound 52C (242 mg, 0.558 mmol) was added10% Pd—C (50 mg), and the mixture was subjected to a catalytic reductionreaction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 60mg (yield 31%) of compound 52.

¹H-NMR (CDCl₃) δ: 3.05 (2H, brs), 3.36 (3H, s), 3.58 (1H, d, J=12 Hz),3.66-3.68 (2H, m), 3.74-3.75 (2H, m), 4.11-4.19 (2H, m), 6.80 (1H, brs),6.90-7.04 (2H, m), 7.30 (3H, brs).

Reference Example 53

First Step

To a DMF (10 ml) solution of compound 1I (1.0 mg, 2.23 mmol) were addedtriethylamine (677 mg, 6.69 mmol) and ethyl chlorocarbonate (729 mg,6.69 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 10 minutes. To the reaction solution were addedmethanesulfonamide (1.06 g, 11.15 mmol) and DMAP (272.4 mg, 2.23 mmol),and the mixture was heated to stir at 80° C. for 2 hours. To thereaction solution was added water, and the mixture was extracted withethyl acetate three times. After the extract was washed with water threetimes, and dried with sodium sulfate, the solvent was distilled off, andthe resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with only chloroform and, then, withchloroform-MeOH (9:1, v/v). Concentration of an objective fractionafforded 535 mg (yield 46%) of compound 53A as an oil.

MS: m/z=463 [M+H]⁺.

Second Step

To a THF (5 ml) solution of compound 53A (535 mg, 0.991 mmol) was added10% Pd—C (218 mg), and the mixture was subjected to a catalyticreduction reaction under hydrogen stream. The catalyst was removed byfiltration, and the filtrate was concentrated. To the resulting residuewas added diisopropyl ether, and the precipitated solid was filtered toobtain 235 mg (yield 53%) of compound 53.

¹H-NMR (DMSO-d₆) δ: 2.99-3.17 (2H, m), 3.27 (3H, s), 3.33 (3H, s),3.53-3.76 (5H, m), 4.06 (1H, dd, J=3.6 Hz, 13.8 Hz), 4.98 (1H, brs),7.14 (2H, d, J=6.6 Hz), 7.19-7.30 (3H, m), 8.07 (1H, s), 12.84 (1H, s),13.24 (1H, s).

Reference Example 54

First Step

To a DMF (10 ml) solution of compound II (1.0 mg, 2.23 mmol) were addedtriethylamine (677 mg, 6.69 mmol) and ethyl chlorocarbonate (729 mg,6.69 mmol) under ice-cooling, and the mixture was stirred at the sametemperature for 10 minutes. The reaction solution was added dropwise toan ice-cooled solution of sodium borohydride (441 mg, 11.7 mmol) inwater (5 ml), and the mixture was stirred at the same temperature for 2hours. To the reaction solution was added 2N hydrochloric acid to stopthe reaction, and the mixture was neutralized with a 2N aqueous sodiumhydroxide solution, and extracted with ethyl acetate three times. Afterthe extract was washed with water three times, and dried with sodiumsulfate, the solvent was distilled off, and the resulting crude productwas dissolved in dichloromethane (5 ml).

To the dichloromethane solution was added manganese dioxide (2.1 g,24.15 mmol), and the mixture was stirred at room temperature for 6hours. After the reaction solution was filtered, and the solvent wasdistilled off, the resulting oil was purified by silica gelchromatography. Elution with ethyl acetate-MeOH (9:1, v/v) andconcentration of an objective fraction afforded 188 mg (yield 19%) ofcompound 54A.

MS: m/z=447 [M+H]⁺.

Second Step

Compound 54A (188 mg, 0.422 mmol) was dissolved in THF (6 ml), 28%aqueous ammonia and iodine (117.7 mg, 0.464 mmol) were added at roomtemperature, and the mixture was stirred at the same temperature for 2hours. To the reaction solution was added an aqueous sodium thiosulfatesolution, and the mixture was extracted with ethyl acetate three times.After the extract was dried with sodium sulfate, the solvent wasdistilled off, and the resulting oil was purified by silica gelchromatography. Elution with ethyl acetate-MeOH (9:1, v/v) andconcentration of an objective fraction afforded 54.7 mg (yield 29%) ofcompound 54B.

¹H-NMR (CDCl₃) δ: 3.05 (2H, d, J=7.5 Hz), 3.33 (3H, s), 3.56-3.79 (5H,m), 3.99 (1H, dd, J=3.6 Hz, 13.8 Hz), 4.08 (1H, brt), 5.33 (1H, d,J=10.2 Hz), 5.46 (1H, d, J=10.2 Hz), 6.83 (1H, s), 6.93-6.97 (2H, m),7.25-7.37 (5H, m), 7.58-7.62 (2H, m).

Third Step

To a toluene (2 ml) solution of compound 54B (216 mg, 0.487 mmol) wereadded sodium azide (95 mg, 1.46 mmol) and triethylamine (201 mg, 1.46mmol), and the mixture was stirred at room temperature for 6 hours. Thereaction solution was extracted with a 2N aqueous sodium hydroxidesolution two times, and the extract was neutralized with 2N hydrochloricacid, and extracted with ethyl acetate three times. After drying of theorganic layer with sodium sulfate, the solvent was distilled off toobtain 65 mg (yield 27%) of compound 54C.

¹H-NMR (CDCl₃) δ: 3.08-3.21 (2H, m), 3.33 (3H, s), 3.55-3.70 (4H, m),3.81-3.90 (1H, m), 3.96-4.01 (1H, m), 4.51 (1H, brt), 5.31 (1H, d,J=10.2 Hz), 5.42 (1H, d, J=10.2 Hz), 7.03-7.05 (2H, m), 7.18-7.37 (6H,m), 7.58-7.61 (2H, m), 8.33 (1H, s).

Fourth Step

To a THF (2 ml)-MeOH (2 ml) solution of compound 54C (500 mg, 1.03 mmol)was added 10% Pd—C (100 mg), and the mixture was subjected to acatalytic reduction reaction under hydrogen stream. The catalyst wasremoved by filtration, and the filtrate was concentrated. The resultingresidue was dissolved in dichloromethane (10 ml), and the solution wasextracted with a 2N aqueous sodium hydroxide solution two times. Afterthe extract was neutralized with 2N hydrochloric acid, the mixture wasextracted with ethyl acetate three times. The organic layer was driedwith sodium sulfate, the solvent was distilled off, and the resultingsolid was washed with diisopropyl ether, and filtered to obtain 55 mg(yield 14%) of compound 54.

¹H-NMR (DMSO-d₆) δ: 3.01-3.19 (2H, m), 3.28 (3H, s), 3.51-3.79 (5H, m),4.09 (1H, dd, J=3.9 Hz, 13.5 Hz), 4.95 (1H, brs), 7.13-7.26 (5H, m),8.20 (1H, s), 12.23 (1H, s).

Reference Example 55

First Step

To a THF (5 ml) solution of compound 1I (500 mg, 1.08 mmol) was added atrimethylsilyldiazomethane 2M hexane solution (1 ml, 2.0 mmol) at roomtemperature, and the mixture was heated to 50° C., and stirred. Afterthe solvent was distilled off, the resulting oil was purified by silicagel chromatography. Elution with n-hexane-ethyl acetate (1:1, v/v) andconcentration of objective fraction afforded 115 mg (yield 22%) ofcompound 55A.

¹H-NMR (CDCl₃) δ: 3.06 (2H, d, J=7.5 Hz), 3.31 (3H, s), 3.51-3.72 (5H,m), 3.81 (3H, s), 3.98 (1H, dd, J=3.6 Hz), 13.5 Hz), 4.11 (1H, brt),5.22 (1H, d, J=9.6 Hz), 5.46 (1H, d, J=9.6 Hz), 6.99-7.02 (2H, m),7.26-7.37 (6H, m), 7.46 (1H, s), 7.65-7.69 (2H, m).

Second Step

Compound 55A (210 mg, 0.441 mmol) was dissolved in THF (2 ml), 10% Pd—C(85.7 mg) was added, and the mixture was subjected to a catalyticreduction reaction under hydrogen stream. The catalyst was removed byfiltration, and the filtrate was concentrated. The resulting residue waswashed with diisopropyl ether ether to obtain 50 mg (yield 23%) ofcompound 55.

¹H-NMR (CDCl₃) δ: 1.55 (2H, d, J=7.5 Hz), 3.37 (3H, s), 3.59-3.84 (5H,m), 4.23-4.32 (2H, m), 7.00 (2H, dd, J=1.5 Hz, 6.9 Hz), 7.23-7.32 (3H,m), 7.39 (1H, s), 12.31 (1H, brs).

Reference Example 56

First Step

A DMF (5 ml) solution of compound 2D (424 mg, 0.787 mmol) wasice-cooled, and triethylamine (327 ul, 2.36 mmol) and, subsequently,ethyl chloroformate (150 ul, 1.57 mmol) were added. After the reactionsolution was stirred at room temperature for 10 minutes, it wasice-cooled again, sodium azide (154 mg, 2.36 mmol) was added, and themixture was stirred for 1 hour. To the reaction solution were addeddichloromethane, water and a small amount of methanol, thedichloromethane layer was separated, and the aqueous layer was extractedwith dichloromethane once. The combined extracts were concentrated,methanol (8 ml) was added to the resulting residue, the mixture wasstirred at 50° C. for 3 hours, and the solvent was distilled off. Theresulting oil was purified by silica gel column chromatography. Thematerials were eluted firstly with n-hexane-ethyl acetate (1:1, v/v)and, then, with only ethyl acetate. Concentration of objective fractionafforded 160 mg of compound 56A as a white solid.

¹H-NMR (CDCl₃) δ: 3.08-3.18 (4H, m), 3.35-3.49 (3H, m), 3.68 (3H, s),3.98 (2H, dt, J=23.1, 5.6 Hz), 4.32 (1H, d, J=11.3 Hz), 4.59 (1H, d,J=11.3 Hz), 5.37 (2H, dd, J=12.0, 10.4 Hz), 6.98-7.70 (15H, m).

MS: m/z=568.25 [M+H]⁺.

Second Step

Compound 56A (160 mg, 0.102 mmol) was dissolved in EtOH (10 mL), a 2Naqueous sodium hydroxide solution (14 ml) was added, and the mixture wasstirred at 60° C. for 2 hours. After the reaction solution wasconcentrated under reduced pressure, the residue was distributed betweendichloromethane and water. The dichloromethane layer was separated, andthe aqueous layer was extracted with dichloromethane three times. Thesolvent was distilled off to obtain compound 56B.

¹H-NMR (CDCl₃) δ: 2.97-3.06 (1H, m), 3.15 (3H, s), 3.38-3.44 (3H, m),3.71 (2H, s), 3.93-3.99 (2H, m), 4.35 (2H, dd, J=19.3, 11.1 Hz), 5.37(2H, dd, J=31.6, 10.1 Hz), 6.04 (1H, s), 6.98 (2H, dd, J=6.4, 2.9 Hz),7.17 (4H, t, J=3.3 Hz), 7.28-7.69 (12H, m).

MS: m/z=509.23 [M+H]⁺.

Third Step

Compound 56B (56 mg, 0.11 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas subjected to toluene azeotropy, and the resulting residue waspurified using an LCMS fractionating device. The eluted solvent wasdistilled off, isopropyl ether was added to the residue, and theprecipitated solid was filtered. Washing with isopropyl ether and dryingafforded 7 mg of compound 56.

MS: m/z=420.07 [M+H]⁺.

Reference Example 57

First Step

To a THF (1 mL) solution of compound 56B (25 mg, 0.049 mmol) were addedtriethylamine (20 uL, 0.15 mmol) and, subsequently, acetic acidanhydride (7.0 ul, 0.074 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 15 minutes. Then, 4-fluorobenzyl amine(330 mg, 1.75 mmol) was added, and the mixture was stirred for 7 hours.Further, triethylamine (20 uL, 0.15 mmol) and, subsequently, acetic acidanhydride (7.0 ul, 0.074 mmol) were added, and the mixture was stirredovernight. To the reaction solution were added water, ethyl acetate, andbrine, the ethyl acetate layer was separated, and the aqueous layer wasextracted with ethyl acetate. To the combined extracts was added sodiumsulfate, and filtration and concentration afforded 18 mg of compound 57Aas a white solid.

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 3.09-3.14 (4H, m), 3.41-3.45 (3H, m),3.95-4.02 (2H, m), 4.31 (1H, d, J=11.4 Hz), 4.59 (1H, d, J=12.4 Hz),5.36 (2H, s), 7.00 (2H, d, J=4.0 Hz), 7.11-7.16 (3H, m), 7.36 (7H, tt,J=14.5, 5.1 Hz), 7.62 (2H, t, J=7.3 Hz), 8.02 (1H, s), 8.18 (1H, s).

MS: m/z=552.20 [M+H]⁺.

Second Step

Compound 57A (21 mg, 0.038 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 3.5 hours. The reactionmixture was subjected to toluene azeotropy, isopropyl ether was added tothe resulting residue, and the precipitated solid was filtered. Washingwith isopropyl ether, and drying afforded 10 mg of compound 57.

¹H-NMR (CDCl₃) δ: 2.12 (3H, s), 3.20 (3H, s), 3.39-3.60 (4H, m),3.76-3.86 (1H, m), 4.08 (1H, dd, J=13.7, 3.7 Hz), 4.31 (1H, d, J=11.5Hz), 4.68 (1H, dd, J=8.5, 4.3 Hz), 6.96-7.19 (4H, m), 7.30-7.44 (6H, m),8.11 (1H, s).

MS: m/z=462.20 [M+H]⁺.

Reference Example 58

According to Reference example 57, compound 58 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 3.20 (3H, s), 3.41-3.54 (3H, m), 3.60-3.68 (2H, m),3.73-3.85 (1H, m), 4.12 (1H, dt, J=14.0, 3.5 Hz), 4.31 (1H, d, J=11.4Hz), 4.68 (1H, dd, J=11.4, 2.6 Hz), 6.95-7.21 (5H, m), 7.39 (5H, dt,J=26.9, 7.6 Hz), 7.94 (1H, s), 8.88 (1H, s).

MS: m/z=516.10 [M+H]⁺.

Reference Example 59

According to Reference example 57, compound 59 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 3.21 (3H, s), 3.43-3.63 (4H, m), 3.82 (1H, d, J=14.0Hz), 4.12 (1H, dd, J=8.3, 4.2 Hz), 4.35 (1H, d, J=11.2 Hz), 4.74 (1H, d,J=8.3 Hz), 6.90-7.18 (5H, m), 7.34-7.60 (8H, m), 7.82 (2H, d, J=6.8 Hz),8.34 (1H, s), 8.89 (1H, s).

MS: m/z=523.21 [M+H]⁺.

Reference Example 60

To compound 56B (30 mg, 0.059 mmol) were added formic acid (1.0 mL, 26mmol) and, subsequently, a 37% formaldehyde solution (0.5 mL, 6.7 mmol),and the mixture was stirred at 100° C. for 7 hours. The reactionsolution was subjected to toluene azeotropy, DMSO was added, insolubleswere filtered and, thereafter, purification was performed using an LCMSfractionating device. The eluted solvent was distilled off, isopropylether was added to the residue, and the precipitated solid was filtered.Washing with isopropyl ether, and drying afforded 3 mg of compound 60.

¹H-NMR (CDCl₃) δ: 2.37 (6H, s), 3.18 (3H, s), 3.29-3.66 (4H, m), 3.82(1H, d, J=12.5 Hz), 4.06-4.15 (1H, m), 4.31 (1H, d, J=11.7 Hz), 4.54(1H, d, J=8.1 Hz), 5.97 (1H, s), 7.01 (2H, dd, J=6.4, 2.8 Hz), 7.17 (3H,t, J=2.9 Hz), 7.32-7.45 (6H, m).

MS: m/z=448.15 [M+H]⁺.

Reference Example 61

First Step

Compound 56B (50 mg, 0.098 mmol) was dissolved in THF (1 mL), Boc2O(0.068 mL, 0.29 mmol) and, subsequently, DMAP (6.0 mg, 0.049 mmol) wereadded, and the mixture was stirred at room temperature for 5 hours. Tothe reaction solution were added water and ethyl acetate, the ethylacetate layer was separated, and the aqueous layer was extracted withethyl acetate. To the combined extracts was added sodium sulfate, themixture was filtered, and the solvent was distilled off. The resultingresidue was purified by silica gel column chromatography. Concentrationof an objective fraction afforded 20 mg of compound 61A as a colorlesstransparent oil.

MS: m/z=610.50 [M+H]⁺.

Second Step

Compound 61A (20 mg, 0.033 mmol) was dissolved in DMF (1 mL), sodiumhydride (2.6 mg, 0.066 mmol) was added under ice-cooling, the mixturewas stirred for 10 minutes, methyl iodide (4.1 uL, 0.066 mmol) wasadded, and the mixture was stirred at room temperature for 1.5 hours.Ice water, ethyl acetate and brine were added, the ethyl acetate layerwas separated, and the aqueous layer was extracted with ethyl acetate.To the combined extracts was added sodium sulfate, the mixture wasfiltered, and the solvent was distilled off. The resulting residue waspurified by silica gel column chromatography. Concentration of anobjective fraction afforded 13 mg of compound 61B as a white solid.

MS: m/z=624.25 [M+H]⁺.

Third Step

Compound 61B (13 mg, 0.021 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 3 hours. The reactionmixture was subjected to toluene azeotropy, and the resulting residuewas purified using an LCMS fractionating device. The eluted solvent wasdistilled off, isopropyl ether-hexane were added to the residue, and theprecipitated solid was filtered. Washing with isopropyl ether, anddrying afforded 7.5 mg of compound 61.

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 3.26 (3H, s), 3.46-3.70 (4H, m), 4.23(1H, d, J=11.0 Hz), 4.58-4.60 (1H, brm), 5.41-5.44 (1H, brm), 6.28 (1H,brs), 6.99 (2H, brs), 7.13 (3H, brs), 7.31-7.46 (6H, m).

MS: m/z=434.10 [M+H]⁺.

Reference Example 62

First Step

Compound 2D (112 mg, 0.208 mmol) was dissolved in DMF (2 mL),triethylamine (0.144 ml, 1.04 mmol) and, subsequently, ethylchloroformate (0.040 mL, 0.42 mmol) were added under ice-cooling, themixture was stirred at room temperature for 10 minutes, thereafter,N,O-dimethylhydroxyamine hydrochloride (41 mg, 0.42 mmol) and,subsequently, DMAP (3 mg, 0.02 mmol) were added, and the mixture wasstirred at room temperature for 1 hour. To the reaction solution wereadded water and ethyl acetate, the ethyl acetate layer was separated,and the aqueous layer was extracted with ethyl acetate. To the combinedextracts was added sodium sulfate, the mixture was filtered, and thesolvent was distilled off. The resulting residue was purified by silicagel column chromatography. Concentration of an objective fractionafforded 127 mg of crude purified product 62A as a yellow oil.

MS: m/z=582.20 [M+H]⁺.

Second Step

Compound 62A (137 mg, 0.236 mmol) was dissolved in THF (8 mL), a 2M THFsolution of methylmagnesium bromide (0.444 ml, 0.471 mmol) was added at−78° C. under nitrogen stream, and the mixture was stirred for 30minutes while temperature was raised to −50° C. To the reaction solutionwas added 1M hydrochloric acid (4 ml), the mixture was stirred at 0° C.for 20 minutes, ethyl acetate was added, the ethyl acetate layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Thecombined extracts were neutralized with an aqueous saturated sodiumbicarbonate solution, sodium sulfate was added to the organic layer, themixture was filtered, and the solvent was distilled off. The resultingresidue was purified by silica gel column chromatography. Concentrationof an objective fraction afforded 67 mg of compound 62B as a yellow oil.

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 3.01-3.14 (1H, m), 3.16 (3H, s),3.37-3.54 (3H, m), 3.91-4.07 (2H, m), 4.28 (1H, d, J=11.3 Hz), 4.50-4.60(1H, m), 5.42 (2H, d, J=1.2 Hz), 6.97-6.99 (2H, m), 7.14-7.17 (4H, m),7.31-7.45 (8H, m), 7.65 (2H, d, J=6.5 Hz).

MS: m/z=537.20 [M+H]⁺.

Third Step

Compound 62B (67 mg, 0.13 mmol) was dissolved in dichloromethane (4 mL),mCPBA (32 mg, 0.19 mmol) was added at 0° C. under nitrogen stream, andthe mixture was stirred at room temperature for 3 hours. The reactionsolution was ice-cooled, an aqueous sodium thiosulfate solution, andethyl acetate were added, the ethyl acetate layer was separated, and theaqueous layer was extracted with ethyl acetate. The combined extractswere neutralized with an aqueous saturated sodium bicarbonate solution,sodium sulfate was added to the organic layer, the mixture was filtered,and the solvent was distilled off to obtain 64 mg of compound 62C.

MS: m/z=553.23 [M+H]⁺.

Fourth Step

Compound 62C (64 mg, 0.12 mmol) was dissolved in ethanol (8 mL), and thesolution was heated to reflux for 4 hours. The reaction solution wasconcentrated, and the resulting residue was purified by silica gelcolumn chromatography. Concentration of an objective fraction afforded42 mg of compound 62D.

¹H-NMR (CDCl₃) δ: 2.93-3.09 (1H, m), 3.16 (3H, s), 3.33-3.53 (4H, m),3.90-4.07 (2H, m), 4.29-4.47 (2H, m), 5.41 (2H, q, J=10.4 Hz), 6.34 (1H,s), 6.95-6.99 (2H, m), 7.12-7.21 (4H, m), 7.33-7.42 (8H, m), 7.64 (2H,d, J=6.9 Hz).

MS: m/z=511.21 [M+H]⁺.

Fifth Step

Compound 62D (41 mg, 0.080 mmol) was dissolved in DMF (1 mL), sodiumhydride (6.4 mg, 0.16 mmol) was added under ice-cooling, the mixture wasstirred for 10 minutes, methyl iodide (0.010 ml, 0.16 mmol) was added,and the mixture was stirred at room temperature for 1.5 hours. To thereaction solution were added ice water and ethyl acetate, the ethylacetate layer was separated, and the aqueous layer was extracted withethyl acetate. To the combined extracts was added sodium sulfate, themixture was filtered, and the solvent was distilled off. The resultingresidue was purified by silica gel column chromatography. Concentrationof an objective fraction afforded 41 mg of compound 62E as a whitesolid.

¹H-NMR (CDCl₃) δ: 2.99-3.09 (1H, m), 3.16 (3H, s), 3.25 (3H, s),3.32-3.38 (1H, m), 3.42-3.50 (2H, m), 3.94-4.03 (2H, m), 4.28 (1H, d,J=11.3 Hz), 4.43 (1H, brs), 5.40 (2H, dd, J=28.3, 10.2 Hz), 6.01 (1H,s), 6.90-7.19 (5H, m), 7.28-7.44 (8H, m), 7.66 (2H, d, J=6.4 Hz).

MS: m/z=525.21 [M+H]⁺.

Sixth Step

Compound 62E (40 mg, 0.076 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 30 minutes. The reactionmixture was subjected to toluene azeotropy, and the resulting residuewas purified using an LCMS fractionating device. The eluted solvent wasdistilled off, ethyl acetate-isopropyl ether-hexane were added to theresidue, and the precipitated solid was filtered. Washing with isopropylether, and drying afforded 7.1 mg of compound 62 as a pink solid.

¹H-NMR (CDCl₃) δ: 3.17 (3H, s), 3.22 (3H, s), 3.40-3.53 (4H, m),3.63-3.71 (1H, m), 4.24 (1H, d, J=11.5 Hz), 4.45 (1H, d, J=13.3 Hz),4.60 (1H, d, J=11.2 Hz), 6.08 (1H, d, J=11.7 Hz), 6.96-6.99 (2H, brm),7.13-7.17 (3H, m), 7.30-7.43 (5H, m).

MS: m/z=435.15 [M+H]⁺.

Reference Example 63

First Step

Compound 2D (164 mg, 0.304 mmol) was dissolved in diphenyl ether (1 mL),the mixture was stirred at 245° C. for 1 hour using a microwaveapparatus and, thereafter, the reaction solution was purified by silicagel column chromatography. Concentration of an objective fractionafforded 72 mg of compound 63A as a brown solid.

¹H-NMR (CDCl₃) δ: 2.92-3.01 (1H, m), 3.16 (3H, s), 3.32-3.50 (3H, m),3.90-4.46 (4H, m), 5.42 (2H, dd, J=26.1, 10.3 Hz), 5.94 (1H, d, J=7.4Hz), 6.28 (1H, d, J=7.5 Hz), 6.96-6.99 (2H, m), 7.15-7.19 (3H, m),7.28-7.44 (8H, m), 7.62-7.65 (2H, m).

MS: m/z=495.21 [M+H]⁺.

Second Step

To a dichloromethane (4 mL) solution of compound 63A (21 mg, 0.042 mmol)was added NBS (11 mg, 0.062 mmol), and the mixture was heated to refluxfor 1 hour. The reaction solution was allowed to cool, and purified bysilica gel column chromatography. Concentration of an objective fractionafforded 26 mg of compound 63B as a white solid.

¹H-NMR (CDCl₃) δ: 3.01-3.09 (1H, m), 3.16 (3H, s), 3.35-3.53 (3H, m),3.92-4.47 (4H, m), 5.41 (2H, dd, J=32.6, 10.0 Hz), 6.72 (1H, s),6.97-7.00 (2H, brm), 7.20-7.22 (3H, m), 7.30-7.46 (8H, m), 7.66-7.70(2H, m).

MS: m/z=573.20 [M+H]⁺.

Third Step

Compound 63B (10 mg, 0.017 mmol) was dissolved in TFA (3 mL), and themixture was stirred at room temperature for 50 minutes. The reactionmixture was subjected to toluene azeotropy, isopropyl ether was added tothe resulting residue, and the precipitated solid was filtered. Washingwith isopropyl ether, and drying afforded 1.4 mg of compound 63 as anorange solid.

MS: m/z=483.15 [M+H]⁺.

Reference Example 64

First Step

To a DMF solution (2 mL) of compound 63B (20 mg, 0.035 mmol) were addedpyrazole-4-boronic acid pinacol ester (36 mg, 0.19 mmol) and,subsequently, potassium carbonate (29 mg, 0.21 mmol) and, thereafter,tetrakistriphenylphosphinepalladium (24 mg, 0.021 mmol) was added undernitrogen atmosphere, and the mixture was stirred at 110° C. for 8.5hours. After the reaction solution was concentrated, ethyl acetate andmethanol were added, and insolubles were removed. The filtrate wasconcentrated, and the resulting residue was purified by silica gelcolumn chromatography. Concentration of an objective fraction afforded18 mg of compound 64A as a white solid.

MS: m/z=561.30 [M+H]⁺.

Second Step

Compound 64A (14 mg, 0.025 mmol) was dissolved in TFA (2 mL), and themixture was stirred at room temperature for 30 minutes. The reactionmixture was subjected to toluene azeotropy, and the resulting residuewas purified using an LCMS fractionating device. The eluted solvent wasdistilled off, isopropyl ether was added to the residue, and theprecipitated solid was filtered. Washing with isopropyl ether, anddrying afforded 1.1 mg of compound 64 as an orange solid.

MS: m/z=471.20 [M+H]⁺.

Reference Example 65

First Step

A THF (1.1 L) solution of compound 65A (WO 2006/088173, 20.0 g, 69.6mmol) was retained at 25° C. on a water bath, an aqueous (378 mL)solution of sodium chlorite (25.2 g, 278 mmol) and amidosulfuric acid(27.0 g, 278 mmol) was added dropwise over 30 minutes. The reactionsolution was stirred at the same temperature for 1 hour, andconcentrated under reduced pressure. To the residue were added ice water(100 mL) and diethyl ether (100 mL), and the precipitated solid wasfiltered. The resulting crude purified product was washed with water anddiethyl ether to obtain 20.3 g of compound 65B as a white solid.

¹H-NMR (DMSO-d₆) δ: 3.74 (3H, s), 5.11 (2H, s), 7.31-7.38 (3H, m), 7.48(2H, d, J=7.2 Hz), 8.11 (1H, s), 12.07 (1H, brs).

Second Step

Compound 65B (2.0 g, 6.59 mmol) was dissolved in DMF (340 mL), HATU(2.76 g, 7.25 mmol), methylamine (2 mol/L THF solution, 3.63 mL, 7.25mmol) and triethylamine (9.89 mmol) were added, and the mixture wasstirred at room temperature for 5 hours. The reaction solution wasdistributed between ethyl acetate and water. The ethyl acetate layer wasseparated, and the aqueous layer was extracted with ethyl acetate once.The combined extracts were washed with water and an aqueous saturatedsodium chloride solution, and dried. The solvent was distilled off toobtain 1.66 g of a crude purified product of compound 65C as a whitesolid.

¹H-NMR (DMSO-d₆) δ: 3.38 (3H, brs), 3.75 (3H, s), 5.37 (2H, s),7.34-7.44 (5H, m), 8.10 (1H, s), 8.38 (1H, s), 11.84 (1H, brs).

Third Step

To a DMF (20 mL) solution of compound 65C (1.2 g, 3.79 mmol) were addedpotassium carbonate (1.04 g, 7.59 mmol) andO-(2,4-dinitrophenyl)hydroxylamine (831 mg, 4.17 mmol), and the mixturewas stirred at room temperature for 3 hours. To the reaction solutionwas added water, and the precipitated solid was filtered, and washedwith water to obtain 1.0 g of a crude purified product of compound 65D.

¹H-NMR (DMSO-d₆) δ: 3.74 (3H, s), 3.83 (3H, brs), 5.05 (2H, s), 6.46(2H, brs), 7.31-7.38 (5H, m), 8.20 (1H, s), 8.52 (1H, brs).

Fourth Step

To a DMF (10 mL) solution of compound 65D (1.0 g, 3.02 mmol) were addedparaformaldehyde (109 mg, 3.62 mmol) and acetic acid (0.017 ml, 0.302mmol) at room temperature, and the mixture was stirred at 105° C. for 2hours. The reaction solution was cooled to 0° C., cesium carbonate (3.44g, 10.6 mmol) was added, and the mixture was stirred at room temperaturefor 1 hour. To the reaction solution was added water, and the mixturewas distributed between ethyl acetate and water. The organic layer waswashed with an aqueous saturated sodium chloride solution, and dried.The solvent was distilled off to obtain 120 mg of compound 65E.

MS: m/z=344 [M+H]⁺.

Fifth Step

To a DMF (1 mL) solution of compound 65E (17.0 mg, 0.05 mmol) were addedcesium carbonate (81.4 mg, 0.25 mmol) and methylamine (2 mol/L THFsolution, 0.125 ml, 0.25 mmol), and the mixture was stirred at roomtemperature for 5 hours. The reaction solution was filtered, and thefiltrate was fractionated and purified by LCMS to obtain compound 65F.

MS: m/z=358 [M+H]⁺.

Sixth Step

To a DMF (0.5 mL) solution of compound 65F was added a 2N aqueous sodiumhydroxide solution (0.2 mL), and the mixture was stirred at roomtemperature for 2 hours. To the reaction solution was added ion-exchangeresin DOWEX (50W-X8), and the mixture was filtered, and washed with DMF.After concentration of the filtrate, trifluoroacetic acid (0.5 mL) wasadded, and the mixture was stirred at 80° C. for 4 hours. Afterconcentration of the reaction solution, water and chloroform were added,and the organic layer was separated. The organic layer was concentrated,and fractionation-purified by LCMS to obtain 6.47 mg of compound 65.

MS: m/z=254[M+H]⁺.

According to Reference example 65, compounds of Reference examples 66 to92 shown in Tables 10 to 14 below were synthesized by the sameprocedure.

TABLE 10 Reference example Structure MS Reference example 66

348 Reference example 67

296 Reference example 68

340 Reference example 69

348 Reference example 70

442 Reference example 71

318

TABLE 11 Reference example Structure MS Reference example 72

362 Reference example 73

388 Reference example 74

438 Reference example 75

298 Reference example 76

430 Reference example 77

442

TABLE 12 Reference example Structure MS Reference example 78

442 Reference example 79

454 Reference example 80

438 Reference example 81

492 Reference example 82

443

TABLE 13 Reference example Structure MS Reference example 83

513 Reference example 84

500 Reference example 85

454 Reference example 86

452 Reference example 87

480

TABLE 14 Reference example Structure MS Reference example 88

406 Reference example 89

445 Reference example 90

500 Reference example 91

416 Reference example 92

450

Reference Example 93

According to Reference example 65, compound 93 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 3.34 (3H, s), 3.57-3.68 (2H, m), 3.73 (2H, brs), 4.18(2H, s), 4.75 (2H, brs), 7.06-7.12 (2H, m), 7.21-7.24 (2H, m), 8.10 (1H,s), 11.96 (1H, brs), 14.52 (1H, brs).

Reference Example 94

First Step

Using compound 94A (WO 2007/049675), and according to the same procedureas that of the fifth step of Reference example 65, compound 94B wassynthesized.

¹H-NMR (CDCl₃) δ: 3.00-3.09 (1H, m), 3.18 (3H, s), 3.44 (2H, dd, J=7.55,2.82 Hz), 4.02-4.08 (1H, m), 4.44-4.59 (3H, m), 4.86 (1H, d, J=13.57Hz), 5.25 (1H, s), 5.36 (2H, dd, J=14.87, 9.99 Hz), 6.74-6.84 (2H, m),7.09-7.60 (16H, m), 7.90 (1H, s), 10.07 (H, t, J=5.87 Hz).

Second Step

To a MeCN (20 ml) solution of compound 94B (1.1 g, 1.655 mmol) wereadded DMAP (202 mg, 1.655 mmol) and Boc2O (20 ml, 86 mmol) at roomtemperature under nitrogen stream, and the mixture was heated to refluxfor 5 hours. Further, Boc2O (20 ml, 86 mmol) was added, and the mixturewas heated to reflux for 5 hours. After concentration under reducedpressure, to the residue were added ethanol (20.00 ml) and an aqueoussodium hydroxide solution (40%, 25 ml), and the mixture was stirred atroom temperature for 5 hours. To the reaction mixture were added ethylacetate-water to make the aqueous layer acidic. After extraction withethyl acetate (2×200 mL), the organic layer was washed with an aqueoussaturated sodium chloride solution. After drying with magnesium sulfate,the solvent was distilled off under reduced pressure. The crude productwas purified by silica gel column chromatography (CHC3/MeOH 20:1) toobtain compound 94C. (750 mg, 63%)

¹H-NMR (DMSO-d₆) δ: 3.13 (3H, s), 3.25-3.34 (3H, m), 3.79 (1H, d,J=13.73 Hz), 4.42 (1H, d, J=14.03 Hz), 5.11-5.27 (3H, m), 5.48 (1H, s),7.18-7.21 (5H, m), 7.33-7.49 (6H, m), 7.56-7.58 (2H, m), 7.74 (2H, d,J=7.32 Hz), 8.01 (1H, s).

Third Step

Using compound 94C, and according to the same procedure as that of thetenth step of Reference example 12, compound 94 was synthesized.

¹H-NMR (DMSO-d₆) δ: 3.13 (3H, s), 3.41-3.56 (4H, m), 4.50 (1H, d,J=13.57 Hz), 5.21 (1H, d, J=13.42 Hz), 5.58 (1H, s), 7.16-7.50 (8H, m),7.72 (2H, d, J=7.32 Hz), 7.93 (1H, s), 12.12 (1H, s).

Reference Example 95

First Step

Compound 95A (WO 2006/116764, 1 g, 4.06 mmol) was dissolved in 28%aqueous ammonia, and the solution was stirred at room temperature for 12hours. After concentration of the reaction solution, the resultingresidue was neutralized with 2N hydrochloric acid, and the precipitatedsolid was suspended in ethyl acetate, filtered, and dried to obtain 1.14g (yield 100%) of compound 95B.

¹H-NMR (DMSO-d₆) δ: 5.14 (2H, s), 7.31 (1H, d, J=6.6 Hz), 7.34-7.41 (3H,m), 7.45-7.51 (2H, m), 8.17 (1H, d, J=6.6 Hz).

Second Step

To a DMF (10 ml) solution of the compound 95B (3.00 g, 10.65 mmol) wereadded WSC HCl (3.06 g, 15.98 mmol) and HOBt (1.58 g, 11.7 mmol) at roomtemperature, the mixture was stirred for 10 minutes, and a methylamine33 wt % ethanol solution (1.50 g, 15.98 mmol) was added dropwise. Afterthe reaction solution was stirred at the same temperature for 2 hours,water was added, and the mixture was extracted with chloroform fivetimes. The extract was dried with sodium sulfate, the solvent wasdistilled off, and the resulting oil was purified by silica gelchromatography. From a fraction eluted with ethyl acetate-MeOH (6:4,v/v), 2.62 g (yield 95%) of compound 95C was obtained as a solid.

¹H-NMR (CDCl₃) δ: 2.77 (3H, d, J=4.8 Hz), 5.49 (2H, s), 6.57 (1H, d,J=6.9 Hz), 7.25-7.43 (5H, m), 7.48 (1H, t, J=6.0 Hz), 8.23 (1H, brs),9.77 (1H, brs).

Third Step

To a DMF (10 ml) solution of the compound 95C (2.62 g, 10.14 mmol) wassuspended potassium carbonate (4.20 g, 30.42 mmol) at room temperature,the suspension was stirred for 5 minutes,0-(2,4-dinitrophenyl)hydroxylamine (3.03 g, 15.21 mmol) was added, andthe mixture was stirred at the same temperature for 3 hours. To thereaction solution was added water, the mixture was extracted withchloroform five times, and the extract was dried with sodium sulfate.After the solvent was distilled off, the resulting oil was purified bysilica gel chromatography. From a fraction eluted with ethylacetate-MeOH (6:4, v/v), 1.41 g (yield 51%) of compound 95D was obtainedas a solid.

¹H-NMR (CDCl₃) δ: 2.62 (3H, d, J=5.1 Hz), 5.06 (2H, s), 5.22 (2H, s),6.18 (1H, d, J=7.8 Hz), 7.25-7.36 (5H, m), 5.89 (1H, d, J=7.8 Hz), 7.57(1H, q, J=5.1 Hz).

Fourth Step

A toluene (10 ml) solution of the compound 95D (1.0 g, 3.66 mmol) wereadded paraformaldehyde (109.9 mg, 3.66 mmol) and acetic acid (22 mg,0.37 mmol), and the mixture was heated to stir at 100° C. for 40minutes. After cooling, the solvent was distilled off, the residue wasdissolved in DMF (10 ml) without purification, cesium carbonate (3.58 g,10.98 mmol) was added under ice-cooling, and the mixture was stirred for10 minutes. To the reaction solution was added benzohydryl bromide (1.36g, 5.49 mmol), the mixture was stirred at room temperature for 3 hours,water was added, and the mixture was extracted with ethyl acetate threetimes. The extract was washed with water three times, and dried withsodium sulfate. The solvent was distilled off, and the resulting oil waspurified by silica gel chromatography. From a fraction eluted with ethylacetate-MeOH (9:1, v/v), 1.26 g (yield 71%) of compound 95E was obtainedas a solid.

¹H-NMR (CDCl₃) δ: 2.91 (3H, s), 4.26 (1H, d, J=13.2 Hz), 4.77 (1H, d,J=13.2 Hz), 5.12 (1H, s), 5.42 (1H, J=13.2 Hz), 5.45 (1H, d, J=13.2 Hz),5.82 (1H, J=7.5 Hz), 6.71 (1H, d, J=7.5 Hz), 7.10-7.23 (5H, m),7.27-7.46 (6H, m), 7.52 (2H, d, J=6.9 Hz), 7.60-7.64 (2H, m).

Fifth Step

Compound 95E (100 mg, 0.221 mmol) was dissolved in trifluoroacetic acid(2 ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 50 mg (yield 63%) of compound 95.

¹H-NMR (CDCl₃) δ: 2.95 (3H, s), 4.36 (1H, d, J=13.2 Hz), 4.95 (1H, d,J=13.2 Hz), 5.22 (1H, s), 5.71 (1H, d, J=7.8 Hz), 6.75 (1H, d, J=7.8Hz), 7.21 (5H, brs), 7.33-7.47 (4H, m), 7.55 (2H, d, J=6.6 Hz).

According to Reference example 95, the following compounds weresynthesized by the same procedure.

Reference Example 96

¹H-NMR (CDCl₃) δ: 3.12-3.18 (1H, m), 3.21 (3H, s), 3.38-3.52 (2H, m),3.81 (1H, ddd, J=3.3 Hz, 4.2 Hz, 14.1 Hz), 4.52 (1H, d, J=13.2 Hz), 5.00(1H, d, J=13.2 Hz), 5.28 (1H, s), 5.71 (1H, d, J=7.8 Hz), 6.74 (1H, d,J=7.8 Hz), 7.14-7.21 (5H, m), 7.32-7.46 (3H, m), 7.53 (2H, d, J=7.5 Hz).

Reference Example 97

¹H-NMR (CDCl₃) δ: 2.99-3.06 (0.54H, m), 3.18-3.23 (3.9H, m), 3.42-3.54(2.5H, m), 3.86-3.91 (0.42H, m), 4.03-4.08 (0.58H, m), 4.37 (0.58H, d,J=13.5 Hz), 4.54 (0.42H, d, J=13.8 Hz), 4.98 (0.58H, d, J=13.5 Hz), 5.08(0.42H, d, J=13.8 Hz), 5.36 (0.58H, s), 5.43 (0.42H, s), 5.70-5.77 (1H,m), 6.77 (0.42H, d, J=7.5 Hz), 6.94 (0.58H, d, J=7.8 Hz), 7.08-7.53 (6H,m), 7.60-7.78 (2H, m), 8.55 (0.58H, d, J=4.2 Hz), 8.72 (0.42H, d, J=3.9Hz).

Reference Example 98

¹H-NMR (CDCl₃) δ: 0.930 (3H, d, J=6.9 Hz), 1.09 (3H, d, J=6.9 Hz), 4.58(1H, d, J=12.6 Hz), 4.79 (1H, d, J=12.6 Hz), 4.83-4.90 (1H, m), 5.20(1H, s), 5.67 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.5 Hz), 7.07-7.09 (2H,m), 7.13-7.19 (3H, m), 7.34-7.46 (3H, m), 7.52 (1H, d, J=7.5 Hz).

Reference Example 99

¹H-NMR (CDCl₃) δ: 3.30 (3H, s), 3.49 (1H, brs), 3.54-3.56 (2H, m), 3.73(1H, brs), 4.11 (2H, brs), 4.25 (1H, brs), 4.78 (1H, brs), 6.00 (1H, d,J=7.5 Hz), 8.33 (1H, d, J=7.5 Hz), 7.19-7.24 (3H, m), 7.34-7.37 (2H, m),7.38-7.48 (4H, m).

Reference Example 100

¹H-NMR (CDCl₃) δ: 4.32 (1H, d, J=14.7 Hz), 4.41 (1H, d, J=12.9 Hz), 4.69(1H, d, J=14.7 Hz), 4.88 (1H, d, J=12.9 Hz), 4.97 (1H, s), 5.68 (1H, d,J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 6.91-6.98 (2H, m), 7.05-7.08 (2H, m),7.12-7.20 (7H, m), 7.30-7.32 (4H, m).

Reference Example 101

¹H-NMR (CDCl₃) δ: 3.35 (3H, s), 3.66-3.69 (3H, m), 3.89 (1H, brs), 4.51(1H, brs), 4.64 (2H, brs), 5.05 (1H, brs), 5.89 (1H, d, J=7.5 Hz), 6.58(1H, d, J=7.5H), 7.11 (1H, d, J=7.2 Hz), 7.26-7.40 (1H, m), 7.54-7.62(2H, m), 7.86-7.93 (2H, m), 8.13 (1H, d, J=8.4 Hz).

Reference Example 102

¹H-NMR (CDCl₃) δ: 4.54 (1H, d, J=12.9 Hz), 4.56 (2H, s), 4.94 (1H, d,J=12.9 Hz), 5.14 (1H, s), 5.68 (1H, d, J=7.8 Hz), 6.20 (1H, d, J=3.0Hz), 6.25-6.27 (1H, m), 6.72 (1H, d, J=7.8 Hz), 7.10-7.37 (11H, m).

Reference Example 103

¹H-NMR (CDCl₃) δ: 3.33 (3H, s), 3.63-3.66 (2H, m), 3.75 (2H, brs), 4.27(2H, brs), 4.67 (1H, brs), 5.00 (1H, brs), 6.09 (1H, d, J=7.8 Hz), 6.99(1H, d, J=7.8 Hz), 7.18 (1H, d, J=7.8 Hz), 7.27-7.32 (1H, m), 7.66-7.71(1H, m), 8.63-8.65 (1H, m).

Reference Example 104

¹H-NMR (CDCl₃) δ: 3.12-3.22 (1H, m), 3.21 (3H, m), 3.38-3.55 (3H, m),3.74-3.80 (0.55H, m), 3.87-3.94 (0.44H, m), 4.46-4.54 (1H, m), 5.00-5.07(1H, m), 5.30-5.39 (1H, m), 5.70 (0.55H, d, J=7.5 Hz), 5.77 (0.45H, d,J=7.5 Hz), 6.74 (0.55H, d, J=7.8 Hz), 6.81 (0.45H, d, J=7.8 Hz),7.11-7.54 (7.45H, m), 7.90 (0.55H, d, J=7.8 Hz), 8.459-8.783 (2H, m).

Reference Example 105

¹H-NMR (CDCl₃) δ: 3.34 (3H, s), 3.65-3.70 (4H, m), 4.18 (1H, brs), 4.21(1H, brs), 4.48 (1H, brs), 4.98 (1H, brs), 6.12 (1H, d, J=7.8 Hz), 6.97(1H, d, J=7.8 Hz), 7.36 (1H, d, J=7.5 Hz), 7.49 (1H, t, J=7.8 Hz),7.61-7.66 (2H, m).

Reference Example 106

¹H-NMR (CDCl₃) δ: 2.54 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 4.38(2H, brs), 4.77 (2H, brs), 6.27 (1H, d, J=7.5 Hz), 6.96-7.00 (2H, m),7.04-7.09 (3H, m), 7.19-7.33 (5H, m).

Reference Example 107

First Step

To a DMF (30 ml) solution of compound 107A (3.0 g, 9.96 mmol)synthesized according to the method of synthesizing compound 95D wereadded paraformaldehyde (299 mg, 9.96 mmol) and acetic acid (1 ml), andthe mixture was heated to stir at 120° C. for 4 hours. After the solventwas distilled off, to the residue were added ethyl acetate-diisopropylether, and the precipitated solid was filtered to obtain 2.85 g (yield91%) of compound 107B.

¹H-NMR (CDCl₃) δ: 1.19 (6H, J=6.6 Hz), 4.34 (2H, J=7.5 Hz), 4.72-4.86(1H, m), 5.30 (2H, s), 5.49 (1H, t, J=7.5 Hz), 6.36 (1H, d, J=7.8 Hz),7.26-7.35 (4H, m), 7.37 (1H, d, J=7.8 Hz), 7.55-7.58 (2H, m).

Second Step

To an acetic acid (2 ml) solution of compound 107B (100 mg, 0.319 mmol)were added 96% sulfuric acid (0.5 ml) and bis(3-chlorophenyl)methanol(242.3 mg, 0.957 mmol) at room temperature, and the mixture was stirredat 80° C. for 2 hours. After the reaction solution was cooled to roomtemperature, water was added, and the mixture was extracted with ethylacetate three times. The organic layer was washed with water once, anddried with sodium sulfate. After the solvent was distilled off, to theresidue was added diisopropyl ether, and the precipitated solid wasfiltered to obtain 42 mg (yield 29%) of compound 107.

¹H-NMR (CDCl₃) δ: 0.953 (3H, d, J=3.9 Hz), 1.12 (3H, d, J=4.2 Hz), 4.51(1H, 13.5 Hz), 4.83 (1H, d, J=13.5 Hz), 4.83-4.92 (1H, m), 5.18 (1H, s),5.74 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.8 Hz), 6.90 (1H, d, J=7.5 Hz),7.12 (2H, dd, J=7.2 Hz, 8.1 Hz), 7.19-7.22 (1H, m), 7.37-7.41 (3H, m),7.55 (1H, s).

According to Reference example 107, the following compounds weresynthesized by the same procedure.

Reference Example 108

¹H-NMR (CDCl₃) δ: 0.465-0.549 (1H, m), 0.642-0.738 (1H, m), 0.754-0.907(2H, m), 2.71-2.79 (1H, m), 2.86 (1H, ddd, J=4.8 Hz, 5.7 Hz, 14.7 Hz),3.01 (2H, ddd, J=4.2 Hz, 16.0 Hz, 16.8 Hz), 3.88 (1H, ddd, J=4.8 Hz, 5.1Hz, 16.8 Hz), 4.08-4.14 (1H, m), 4.16 (1H, d, J=12.9 Hz), 4.70 (1H, d,J=12.9 Hz), 4.96 (1H, s), 5.75 (1H, d, J=7.8 Hz), 6.58 (1H, d, J=7.8Hz), 6.61 (1H, d, J=7.5 Hz), 6.92 (1H, dd, J=6.0 Hz, 7.5 Hz), 7.11-7.80(6H, m).

Reference Example 109

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=6.9 Hz), 1.18 (3H, d, J=6.9 Hz), 2.82(1H, ddd, J=4.5 Hz, 4.8 Hz, 14.1 Hz), 3.08 (1H, ddd, J=4.2 Hz, 13.2 Hz,17.7 Hz), 3.53 (1H, ddd, J=4.2 Hz, 4.5 Hz, 17.7 Hz), 4.27 (1H, d, J=12.9Hz), 4.26-4.37 (1H, m), 4.62-4.71 (1H, m), 4.68 (1H, d, J=12.9 Hz), 5.05(1H, s), 5.71 (1H, d, J=7.5 Hz), 6.63 (2H, d, J=7.2 Hz), 6.90 (1H, t,J=7.5 Hz), 7.08-7.63 (6H, m).

Reference Example 110

¹H-NMR (CDCl₃) δ: 3.16-3.28 (1H, m), 3.22 (3H, s), 3.46-3.50 (2H, m),3.86 (1H, ddd, J=3.6 Hz, 3.6 Hz, 14.4 Hz), 4.47 (1H, d, J=13.2 Hz), 5.01(1H, d, J=13.2 Hz), 5.30 (1H, s), 5.76 (1H, d, J=7.5 Hz), 6.72 (1H, d,J=7.5 Hz), 6.90 (2H, t, J=8.4 Hz), 7.06-7.18 (4H, m), 7.51 (2H, dd,J=5.4 Hz, 8.7 Hz).

Reference Example 111

1H-NMR (CDCl₃) δ: 0.903 (1.3H, d, J=6.9 Hz), 0.982 (1.5H, d, J=6.6 Hz),1.08-1.14 (3.2H, m), 4.55 (1H, dd, J=13.2 Hz, 16.5 Hz), 4.78-4.93 (2H,m), 5.20 (1H, s), 5.66 (0.58H, d, J=7.5 Hz), 5.75 (0.42H, d, J=7.5 Hz),6.67 (0.55H, d, J=7.5 Hz), 6.73 (0.45H, d, J=7.5 Hz), 6.92 (0.45H, d,J=7.2 Hz), 7.04-7.59 (8.6H, m).

Reference Example 112

¹H-NMR (CDCl₃) δ: 3.22 (3H, s), 3.24-3.32 (1H, m), 3.47-3.50 (2H, m),3.84 (1H, ddd, J=3.3 Hz, 3.9 Hz, 14.4 Hz), 4.51 (1H, d, J=13.5 Hz), 5.03(1H, d, J=13.5 Hz), 5.32 (1H, s), 5.77 (1H, d, J=7.8 Hz), 6.80 (1H, d,J=7.8 Hz), 6.84 (1H, d, J=7.8 Hz), 6.93 (2H, t, J=8.4 Hz), 7.06-7.20(2H, m), 7.25-7.29 (2H, m), 7.39-7.47 (1H, m).

Reference Example 113

¹H-NMR (CDCl₃) δ: 0.88 (3H, d, J=6.9 Hz), 1.10 (3H, d, J=6.6 Hz), 2.10(3H, s), 4.62-4.69 (1H, m), 4.79-4.92 (2H, m), 5.32 (1H, s), 5.64(0.74H, 7.5 Hz), 5.72 (0.26H, d, J=7.5 Hz), 6.61 (0.74H, d, J=7.8 Hz),6.82 (0.26H, d, J=7.8 Hz), 6.96-7.52 (8.26H, m), 7.48 (0.74H, d, J=7.5Hz).

Reference Example 114

¹H-NMR (CDCl₃) δ: 0.976 (2H, d, J=6.9 Hz), 1.09-1.14 (3H, m), 5.63(0.74H, d, J=7.8 Hz), 5.65 (0.74H, s), 5.73 (0.26H, d, J=7.8 Hz), 6.20(0.26H, s), 6.65 (0.74H, d, J=7.8 Hz), 6.79 (0.26H, d, J=7.8 Hz),7.05-7.24 (4.26H, m), 7.31-7.56 (4H, m), 8.02 (0.74H, d, J=6.3 Hz).

Reference Example 115

¹H-NMR (CDCl₃) δ: 0.893 (1.2H, d, J=6.6 Hz), 0.958 (1.8H, d, J=6.9 Hz),1.09-1.13 (3H, m), 4.44 (0.56H, d, J=13.2 Hz), 4.63 (0.44H, d, J=13.5Hz), 4.81-4.93 (2H, m), 5.35 (1H, m), 5.67 (0.56H, d, J=7.8 Hz), 5.72(0.44H, d, J=7.8 Hz), 6.67-6.73 (1H, m), 7.03 (1H, d, J=6.6 Hz),7.20-7.51 (5H, m), 7.75 (1H, d, 0.8.4 Hz), 8.06 (0.88H, d, J=8.7 Hz),8.33 (1.1H, d, J=8.7 Hz).

Reference Example 116

¹H-NMR (CDCl₃) δ: 0.91-0.0.948 (3H, m), 1.10-1.14 (3H, m), 3.61-3.68(1H, m), 4.44 (0.56H, d, J=12.9 Hz), 4.59 (0.44H, d, J=12.9 Hz),4.79-4.91 (2H, m), 5.29 (1H, s), 5.67-5.69 (1H, m), 6.63-6.70 (2H, m),6.90-7.81 (8H, m).

Reference Example 117

¹H-NMR (CDCl₃) δ: 3.19-3.28 (1H, m), 3.22 (3H, s), 3.46-3.50 (2H, m),3.85 (1H, ddd, J=3 Hz, 4.2 Hz, 14.4 Hz), 4.47 (1H, d, J=13.2 Hz), 5.01(1H, d, J=13.2 Hz), 5.28 (1H, s), 5.78 (1H, d, J=7.8 Hz), 6.73 (1H, d,J-=7.8 Hz), 7.04 (2H, d, J=8.4 Hz), 7.19 (2H, d, 8.4 Hz), 7.36-7.50 (4H,m).

Reference Example 118

¹H-NMR (CDCl₃) δ: 0.914-0.957 (3H, m), 1.08-1.14 (3H, m), 2.20 (1.4H,s). 2.39 (1.6H, s), 4.56 (0.48H, d, J=4.5 Hz), 4.60 (0.52H, d, J=4.2Hz), 4.77-4.89 (2H, m), 5.16 (1H, s), 5.66-5.70 (1H, m), 6.65-6.69 (1H,m), 6.85-6.91 (1H, m), 6.98-7.10 (2H, m), 7.14-7.19 (2H, m), 7.30-7.39(2H, m), 7.44 (1H, t, J=6.9 Hz), 7.51 (1H, d, J=6.9 Hz).

Reference Example 119

¹H-NMR (CDCl₃) δ: 0.893-0.982 (3H, m), 1.08-1.14 (3H, m), 4.49-4.60 (1H,m), 4.78-4.90 (2H, m), 5.20 (1H, s), 5.65 (0.57H, J=7.5 Hz), 5.76(0.43H, d, J=7.8 Hz), 6.64-6.70 (1H, m), 7.03 (2H, d, J=8.1 Hz),7.10-7.20 (3H, m), 7.28-7.51 (4H, m).

Reference Example 120

¹H-NMR (CDCl₃) δ: 0.526 (3H, d, J=6.9 Hz), 1.01 (3H, d, J=6.6 Hz), 4.69(1H, d, J=13.8 Hz), 4.75-4.83 (1H, m), 4.86 (1H, d, J=13.8 Hz), 5.69(1H, d, J=7.8 Hz), 6.03 (1H, s), 6.70 (1H, d, J=7.8 Hz), 7.16 (5H, s),7.40-7.48 (2H, m), 7.67 (1H, t, J=7.8 Hz), 7.81-7.91 (3H, m), 8.16 (1H,d, J=7.2 Hz).

Reference Example 121

¹H-NMR (CDCl₃) δ: 0.947 (3H, d, J=6.9 Hz), 1.09 (3H, d, J=7.2 Hz), 2.22(3H, s), 2.37 (3H, s), 4.58 (1H, d, J=12.9 Ha), 4.76 (1H, d, J=12.9 Hz),4.78-4.88 (1H, m), 5.13 (1H, s), 5.72 (1H, d, J=7.8 Hz), 6.67 (1H, d,J=7.8 Hz), 6.72 (1H, s), 6.90-6.98 (4H, m), 7.22 (2H, d, J=7.8 Hz), 7.38(2H, d, J=7.8 Hz).

Reference Example 122

¹H-NMR (CDCl₃) δ: 0.932 (3H, d, J=6.6 Hz), 1.12 (3H, d, J=6.9 Hz), 4.44(1H, d, J=13.2 Hz), 4.86 (1H, d, J=13.2 Hz), 4.87-4.93 (1H, m), 5.38(1H, s), 5.67 (1H, d, J=7.8 Hz), 6.67 (1H, d, J=7.8 Hz), 7.21-7.24 (1H,m), 7.32-7.40 (2H, m), 7.52 (1H, d, J=7.5 Hz), 7.60-7.72 (2H, m),7.77-7.79 (2H, m).

Reference Example 123

¹H-NMR (CDCl₃) δ: 3.08-3.17 (1H, m), 3.23 (3H, s), 3.40-3.54 (2H, m),3.71 (3H, s), 3.82 (3H, s), 3.95 (1H, ddd, J=3.3 Hz, 3.9 Hz, 14.4 Hz),4.48 (1H, d, J=13.5 Hz), 4.96 (1H, d, J=13.5 Hz), 5.16 (1H, s), 5.76(1H, d, J=7.5 Hz), 6.70 (2H, d, J=9.0 Hz), 6.73 (1H, d, J=7.5 Hz), 6.94(2H, d, J=8.7 Hz), 7.03 (2H, d, J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz).

Reference Example 124

¹H-NMR (CDCl₃) δ: 0.966 (3H, d, J=6.9 Hz), 1.10 (3H, d, J=6.9 Hz), 3.67(3H, s), 3.83 (3H, s), 4.60 (1H, d, J=12.9 Hz), 4.78 (1H, d, J=12.9 Hz),4.80-4.90 (1H, m), 5.13 (1H, m), 5.23 (1H, d, J=7.8 Hz), 6.66 (2H, d,J=7.2 Hz), 6.72-6.87 (2H, m), 6.87-6.90 (1H, m), 7.06-7.11 (3H, m), 7.34(1H, t, J=8.1 Hz).

Reference Example 125

¹H-NMR (DMSO-d₆) δ: 1.05 (2H, d, J=7.0 Hz), 1.15 (1H, d, J=7.5 Hz),2.73-3.63 (8H, m), 4.20-4.93 (4H, m), 5.25 (0.4H, s), 5.30 (0.6H, s),5.46 (1H, d, J=7.8 Hz), 6.68-7.46 (11H, m).

MS: m/z=446 [M+H]⁺.

Reference Example 126

First Step

Compound 95B (1.00 g, 3.55 mmol) and cyclopropanamine (0.492 ml, 7.10mmol) were added to pyridine (20 ml), 1-hydroxybenzotriazole (544 mg,3.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.36 g, 7.10 mmol) were sequentially added, and themixture was stirred at room temperature for 18 hours. After the solventwas distilled off under reduced pressure, the resulting crude productwas purified by silica gel column chromatography (chloroform-methanol,95:5, v/v) and, subsequently, amino column chromatography(chloroform-methanol, 99:1, v/v) to obtain 1.19 g of compound 126A as acolorless solid.

¹H-NMR (CDCl₃) δ: 0.22 (1H, m), 0.70 (2H, m), 2.76-2.83 (1H, m), 5.50(2H, s), 6.59 (1H, dd, J=7.0, 1.9 Hz), 7.44 (5H, d, J=0.7 Hz), 7.53 (1H,dd, J=6.9, 6.2 Hz), 8.30 (1H, brs), 9.71 (1H, brs).

Second Step

Compound 126A (1.19 g, 4.19 mmol) was dissolved in DMF (15 ml),potassium carbonate (2.90 g, 20.1 mmol) was added, and the mixture wasstirred at room temperature for 30 minutes.O-(2,4-dinitrophenyl)hydroxylamine (1.67 g, 8.38 mmol) was added, andthe mixture was stirred at room temperature for 18 hours. To thereaction solution was added chloroform, the precipitated yellowprecipitate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The resulting crude product was purified byamino column chromatography (chloroform-methanol, 97:3→95:5, v/v) toobtain 851 mg of compound 126B as a yellow solid.

¹H-NMR (CDCl₃) δ: 0.41-0.46 (2H, m), 0.76 (2H, m), 2.73-2.81 (1H, m),5.19 (2H, s), 5.61 (2H, s), 6.26 (1H, d, J=7.2 Hz), 7.38 (5H, s), 7.44(1H, d, J=7.8 Hz), 7.70 (1H, s).

Third Step

Compound 126B (847 mg, 2.83 mmol) and paraformaldehyde (255 mg, 8.49mmol) were added to ethanol (12 ml), and the mixture was stirred at 140°C. for 30 minutes under microwave irradiation. The reaction solution wasconcentrated under reduced pressure, the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,97:3→95:5→90:10, v/v) and, subsequently, amino column chromatography(chloroform-methanol, 97:3, v/v), methylene chloride-ethyl ether wereadded, and the precipitated solid was filtered to obtain 665 mg ofcompound 126C as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.61-0.66 (2H, m), 0.87 (2H, m), 2.68-2.76 (1H, m),4.32 (2H, d, J=7.9 Hz), 5.28 (2H, s), 6.33 (1H, d, J=7.7 Hz), 6.45 (1H,t, J=7.7 Hz), 7.33 (3H, m), 7.38 (1H, d, J=7.7 Hz), 7.52 (2H, m).

Fourth Step

Compound 126C (100 mg, 0.321 mmol) was dissolved in DMF (0.5 ml), cesiumcarbonate (314 mg, 0.964 mmol) and (bromomethylene)dibenzene (119 mg,0.482 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was poured into water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas purified by silica gel column chromatography (chloroform-methanol,97:3→95:5, v/v) to obtain 124 mg of compound 126D as a colorless gummysubstance.

¹H-NMR (CDCl₃) δ: 0.37-0.47 (2H, m), 0.74 (2H, m), 2.63-2.68 (1H, m),4.35 (1H, d, J=13.4 Hz), 4.65 (1H, d, J=13.4 Hz), 5.07 (1H, s), 5.40(1H, d, J=10.7 Hz), 5.47 (1H, d, J=10.5 Hz), 5.79 (1H, d, J=7.6 Hz),6.67 (1H, d, J=7.8 Hz), 7.04-7.62 (15H, m).

Fifth Step

To compound 126D obtained in the fourth step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1.5hours. After concentration under reduced pressure, pH was adjusted to 6with sodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 52 mg of compound 126 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: −0.19-−0.06 (1H, m), 0.44-0.54 (1H, m), 0.82 (2H,m), 2.62-2.69 (1H, m), 4.21 (1H, d, J=13.3 Hz), 5.11 (1H, d, J=13.1 Hz),5.32 (1H, s), 5.47 (1H, t, J=11.1 Hz), 7.13 (1H, d, J=7.6 Hz), 7.23 (3H,m), 7.28-7.47 (8H, m), 7.69 (2H, t, J=8.5 Hz).

MS: m/z=388 [M+H]⁺.

Reference Example 127

According to Reference example 126, compound 127 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 0.86 (1.5H, d, J=7.0 Hz), 1.04 (1.5H, d, J=7.2 Hz),3.08 (1.5H, s), 3.16 (1.5H, s), 4.52-5.05 (3H, m), 5.48 (2H, m),7.31-7.47 (9H, m), 7.66 (2H, t, J=8.4 Hz).

MS: m/z=420 [M+H]⁺.

Reference Example 128

First Step

Compound 95B (2.40 g, 8.52 mmol) and ethyl 3-aminopropanoatehydrochloride (2.62 g, 17.0 mmol) were added to pyridine (30 ml),1-hydroxybenzotriazole (1.31 g, 8.52 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.27 g,17.0 mmol) were sequentially added, and the mixture was stirred at roomtemperature for 2 hours. The solvent was distilled off under reducedpressure, and the resulting crude product was purified by amino columnchromatography (chloroform-methanol, 95:5, v/v) to obtain 1.90 g ofcompound 128A as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.1 Hz), 2.48 (2H, t, J=6.4 Hz), 3.58(2H, q, J=6.3 Hz), 4.17 (2H, q, J=7.1 Hz), 5.59 (2H, s), 6.57 (1H, dd,J=7.1, 1.6 Hz), 7.37-7.52 (6H, m), 8.73 (1H, brs), 9.72 (1H, brs).

Second Step

Compound 128A (2.58 g, 7.49 mmol) was dissolved in DMF (30 ml),potassium carbonate (5.18 g, 37.5 mmol) was added, and the mixture wasstirred at room temperature for 30 minutes.O-(2,4-dinitrophenyl)hydroxylamine (2.98 g, 15.0 mmol) was added, andthe mixture was stirred at room temperature for 20 hours. To thereaction solution was added chloroform, the precipitated yellowprecipitate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The resulting crude product was purified byamino column chromatography (chloroform-methanol, 97:3→95:5, v/v) and,subsequently, silica gel column chromatography (chloroform-methanol,95:5→92:8, v/v) to obtain 1.67 g of compound 128B as a yellow solid.

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.2 Hz), 2.42 (2H, t, J=6.6 Hz), 3.43(2H, q, J=6.4 Hz), 4.12 (2H, q, J=7.1 Hz), 5.13 (2H, s), 5.53 (2H, s),6.21 (1H, d, J=7.6 Hz), 7.33 (5H, s), 7.39 (1H, d, J=7.6 Hz), 7.85 (1H,t, J=5.6 Hz).

Third Step

Compound 128B (1.66 g, 4.62 mmol) and paraformaldehyde (416 mg, 13.9mmol) were added to ethanol (20 ml), and the mixture was stirred at 140°C. for 30 minutes under microwave irradiation. The reaction solution wasconcentrated under reduced pressure, the resulting crude product waspurified by amino column chromatography (chloroform-methanol, 99:1-95:5,v/v) to obtain 1.57 g of compound 128C as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.2 Hz), 2.70 (2H, t, J=5.7 Hz), 3.57(2H, t, J=5.8 Hz), 4.13 (2H, q, J=7.1 Hz), 4.50 (2H, d, J=7.9 Hz), 5.27(2H, s), 5.87 (1H, t, J=7.8 Hz), 6.32 (1H, d, J=7.6 Hz), 7.31 (4H, m),7.54 (2H, m).

Fourth Step

Compound 128C (1.00 g, 2.69 mmol) was dissolved in DMF (10 ml), cesiumcarbonate (2.63 g, 8.08 mmol) and (bromomethylene)dibenzene (998 mg,4.04 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was poured into water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas purified by silica gel column chromatography (chloroform/methanol,98:2, v/v) to obtain 500 mg of compound 128D as a colorless gummysubstance.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.3 Hz), 2.46 (1H, m), 2.70-2.80 (1H,m), 2.87-2.96 (1H, m), 4.11 (2H, q, J=7.3 Hz), 4.12 (1H, m), 4.48 (1H,d, J=13.7 Hz), 4.85 (1H, d, J=13.7 Hz), 5.10 (1H, s), 5.47 (2H, s), 5.83(1H, d, J=8.0 Hz), 6.73 (1H, d, J=8.0 Hz), 7.37 (15H, m).

Fifth Step

To compound 128D (40 mg, 0.074 mmol) was added trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 6 with sodiumbicarbonate water and 2N hydrochloric acid, the mixture was extractedwith chloroform, and the extract was dried with sodium sulfate. Afterthe solvent was distilled off under reduced pressure, methylenechloride-ethyl ether were added, and the precipitated solid was filteredto obtain 20 mg of compound 128 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, t, J=7.1 Hz), 2.45-2.58 (3H, m), 3.70 (1H,m), 4.02 (2H, q, J=7.1 Hz), 4.39 (1H, d, J=13.4 Hz), 5.09 (1H, d, J=13.3Hz), 5.48 (1H, d, J=3.2 Hz), 5.51 (1H, s), 7.19-7.38 (7H, m), 7.45 (2H,t, J=7.3 Hz), 7.69 (2H, d, J=7.2 Hz).

MS: m/z=448 [M+H]⁺.

Reference Example 129

First Step

Compound 128D (426 mg, 0.792 mmol) was dissolved in ethanol (3 ml) andTHF (3 ml), a 2N aqueous sodium hydroxide solution (1.19 ml, 2.38 mmol)was added, and the mixture was stirred at room temperature for 1.5hours. To the reaction solution was added 2N hydrochloric acid, and themixture was extracted with chloroform, and dried with sodium sulfate. Tothe resulting crude product were added methylene chloride-ethyl ether,and the precipitated solid was filtered to obtain 359 mg of compound129A as a colorless solid.

Second Step

To compound 129A (40 mg, 0.079 mmol) was added trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 3 with sodiumbicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 25 mg of compound 129 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.31-2.41 (1H, m), 2.57 (1H, m), 3.63-3.72 (1H, m),4.37 (1H, d, J=13.3 Hz), 5.09 (1H, d, J=13.3 Hz), 5.47 (1H, s), 5.50(1H, d, J=7.8 Hz), 7.28 (7H, m), 7.44 (2H, t, J=7.5 Hz), 7.69 (2H, d,J=7.2 Hz), 12.40 (1H, brs).

MS: m/z=420 [M+H]⁺.

Reference Example 130

First Step

Compound 129A (50 mg, 0.098 mmol) was added to DMF (1 ml),1-hydroxybenzotriazole (14 mg, 0.098 mmol), dimethylamine hydrochloride(24 mg, 0.29 mmol), triethylamine (0.048 ml, 0.34 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15mmol) were added, and the mixture was stirred at room temperature for1.5 hours. The reaction solution was poured into water, and the mixturewas extracted with ethyl acetate, washed with sodium bicarbonate water,and dried with sodium sulfate. The solvent was distilled off underreduced pressure to obtain compound 130A as a colorless gummy substance.

Second Step

To compound 130A obtained in the first step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 2hours. After concentration under reduced pressure, pH was adjusted to 6with sodium bicarbonate water and an aqueous ammonium chloride solution,and the mixture was extracted with chloroform, and dried with sodiumsulfate. The solvent was distilled off under reduced pressure,chloroform-ethyl ether were added, and the precipitated solid wasfiltered to obtain 25 mg of compound 130 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.33-2.43 (1H, m), 2.66 (1H, m), 2.78 (3H, s), 2.89(3H, s), 3.56 (2H, m), 4.45 (1H, d, J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz),5.47 (s, 1H), 5.49 (1H, d, J=7.5 Hz), 7.27 (7H, m), 7.44 (2H, t, J=7.3Hz), 7.69 (2H, d, J=7.3 Hz).

Reference Example 131

According to Reference example 130, compound 131 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.60-2.77 (3H, m), 3.94 (1H, m), 4.42 (1H, d, J=13.4Hz), 5.15 (1H, d, J=13.4 Hz), 5.49 (1H, s), 5.55 (1H, d, J=7.2 Hz), 7.07(1H, t, J=7.3 Hz), 7.12-7.49 (13H, m), 7.73 (2H, d, J=7.2 Hz), 10.01(1H, s).

MS: m/z=495 [M+H]⁺.

Reference Example 132

According to Reference example 130, compound 132 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 3.14 (3H, s), 3.65 (4H, m), 4.34 (1H, d, J=13.6 Hz),5.06 (1H, d, J=13.6 Hz), 5.42 (1H, s), 5.53 (1H, d, J=7.5 Hz), 7.42-7.58(16H, m).

MS: m/z=509 [M+H]⁺.

Reference Example 133

According to Reference example 130, compound 133 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.08-1.55 (8H, m), 2.33 (1H, m), 2.68 (1H, m), 4.45(1H, d, J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz), 5.50 (2H, brs), 7.46-7.68(11H, m).

MS: m/z=487 [M+H]⁺.

Reference Example 134

According to Reference example 130, compound 134 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.34-2.40 (1H, m), 2.61-2.77 (1H, m), 3.51-3.69(10H, m), 4.44 (1H, d, J=13.4 Hz), 5.03-5.11 (1H, d, J=13.4 Hz), 5.51(2H, s), 7.18-7.52 (9H, m), 7.69-7.75 (2H, m).

Reference Example 135

First Step

Compound 95B (1.50 g, 5.32 mmol) and tert-butyl2-aminoethyl(methyl)carbamate (1.86 g, 10.7 mmol) were added to pyridine(20 ml), 1-hydroxybenzotriazole (815 mg, 5.32 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04 g,10.7 mmol) were sequentially added, and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was poured into 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate, anddried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting crude product was purified by amino columnchromatography (chloroform-methanol, 95:5, v/v) and, subsequently,silica gel column chromatography (chloroform-methanol, 95:5, v/v) toobtain 1.63 g of compound 135A as a colorless gummy substance.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.82 (3H, s), 3.28 (4H, m), 5.59 (2H,s), 6.57 (1H, d, J=6.0 Hz), 7.46 (6H, m), 8.46 (1H, m), 9.68 (1H, brs).

Second Step

Compound 135A (1.05 g, 2.62 mmol) was dissolved in DMF (15 ml),potassium carbonate (1.81 g, 13.1 mmol) was added, and the mixture wasstirred at room temperature for 30 minutes.O-(2,4-dinitrophenyl)hydroxylamine (1.04 g, 5.23 mmol) was added, andthe mixture was stirred at room temperature for 18 hours. To thereaction solution was added chloroform, the precipitated yellowprecipitate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The resulting crude product was purified byamino column chromatography (chloroform-methanol, 97 3→95:5, v/v) toobtain 887 mg of compound 135B as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.84 (3H, s), 3.38 (4H, m), 5.33 (2H,s), 5.68 (1H, brs), 5.80 (1H, brs), 6.35 (1H, d, J=7.6 Hz), 6.74 (1H,brs), 7.39 (5H, brm), 7.52 (1H, t, J=9.5 Hz).

Third Step

Compound 135B (880 mg, 2.11 mmol) and paraformaldehyde (190 mg, 6.34mmol) were added to ethanol (18 ml), and the mixture was stirred at 140°C. for 30 minutes under microwave irradiation. The reaction solution wasconcentrated under reduced pressure, and the resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,97:3→95 5→90:10 v/v) and, subsequently, amino column chromatography(chloroform-methanol, 97:3, v/v) to obtain 721 mg of compound 135C as acolorless solid.

¹H-NMR (CDCl₃) δ: 1.29 (9H, s), 2.95 (3H, s), 4.38 (2H, brs), 5.33 (2H,brs), 6.36 (1H, d, J=7.6 Hz), 6.85 (1H, t, J=7.4 Hz), 7.33 (4H, m), 7.55(2H, m).

MS: m/z=429 [M+H]⁺.

Fourth Step

Compound 135C (720 mg, 1.68 mmol) was dissolved in DMF (3.5 ml), cesiumcarbonate (1.64 g, 5.04 mmol) and (bromomethylene)dibenzene (623 mg,2.52 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was poured into water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas purified by silica gel column chromatography (chloroform-methanol,97:3→95:5 v/v) to obtain 732 mg of compound 135D.

Fifth Step

To compound 135D (727 mg, 1.22 mmol) was added 4N HCl (ethyl acetatesolution, 10 ml). After the mixture was stirred at room temperature for1 hour, the solvent was distilled off under reduced pressure. Saturatedsodium bicarbonate water was added, the mixture was extracted withchloroform, and the extract was dried with sodium sulfate. The solventwas distilled off under reduced pressure, to the resulting crude productwere added methylene chloride-ethyl ether, and the precipitated solidwas filtered to obtain 575 mg of compound 135E as a colorless solid.

Sixth Step

To compound 135E (50 mg, 0.10 mmol) was added trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1.5 hours.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and an aqueous ammonium chloride solution, andthe mixture was extracted with chloroform, and dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 15 mg of compound 135 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.40 (3H, s), 2.80 (1H, s), 3.12 (3H, m), 3.87 (1H,m), 4.37 (1H, d, J=13.6 Hz), 5.10 (1H, d, J=13.4 Hz), 5.52 (1H, s), 5.53(1H, d, J=5.5 Hz), 7.15-7.70 (11H, m).

MS: m/z=405 [M+H]⁺.

Reference Example 136

First Step

Compound 135E (50 mg, 0.10 mmol) was dissolved in methylene chloride (1ml), triethylamine (0.042 ml, 0.30 mmol) and acetyl chloride (0.011 ml,0.15 mmol) were added, and the mixture was stirred at room temperaturefor 1 hour. The solvent was distilled off under reduced pressure, andthe resulting crude product was purified by silica gel columnchromatography (chloroform-methanol, 97 3→95:5, v/v) and, subsequently,amino column chromatography (chloroform-methanol, 97:3, v/v) to obtain72 mg of compound 136A as a colorless solid.

Second Step

To compound 136A obtained in the first step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1.5hours. After concentration under reduced pressure, pH was adjusted to 6with sodium bicarbonate water and an aqueous ammonium chloride solution,and the mixture was extracted with chloroform, and dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 23 mg of compound 136 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.89 (2H, s), 1.92 (1H, s), 2.73 (1H, s), 2.95 (2H,s), 3.00-3.06 (1H, m), 3.43 (2H, m), 3.80 (1H, m), 4.34 (0.7H, d, J=13.3Hz), 4.45 (0.3H, d, J=13.1 Hz), 5.11 (1H, m), 5.49 (2H, m), 7.20-7.73(11H, m).

Reference Example 137

According to Reference example 136, compound 137 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.95 (3H, s), 3.13-4.07 (4H, m), 4.46 (1H, d, J=13.2Hz), 5.16 (1H, d, J=13.0 Hz), 5.51 (1H, d, J=7.3 Hz), 5.62 (1H, s),7.17-7.78 (16H, m).

MS: m/z=509 [M+H]⁺.

Reference Example 138

According to Reference example 136, compound 138 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.62 (3H, s), 3.03-3.22 (4H, m), 3.72 (2H, d, J=13.3Hz), 4.39 (1H, d, J=13.3 Hz), 5.08 (1H, d, J=13.3 Hz), 5.53 (1H, d,J=7.8 Hz), 5.55 (1H, s), 7.19-7.79 (16H, m).

MS: m/z=545 [M+H]⁺.

Reference Example 139

According to Reference example 136, compound 139 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.72 (3H, s), 2.88 (3H, s), 3.12-3.24 (3H, m),3.75-3.80 (1H, m), 4.37 (1H, d, J=13.0 Hz), 5.10 (1H, d, J=13.4 Hz),5.51 (1H, d, J=7.6 Hz), 5.54 (1H, s), 7.19-7.46 (19H, m), 7.72 (2H, d,J=7.0 Hz).

MS: m/z=483 [M+H]⁺.

Reference Example 140

According to Reference example 136, compound 140 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.88 (3H, s), 2.98-3.12 (3H, m), 3.77 (1H, m), 4.31(1H, d, J=13.3 Hz), 5.13 (1H, d, J=13.3 Hz), 5.51 (1H, s), 5.52 (1H, d,J=7.6 Hz), 7.13-7.46 (9H, m), 7.71 (2H, d, J=7.2 Hz).

MS: m/z=469 [M+H]⁺.

Reference Example 141

According to Reference example 136, compound 141 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.07 (9H, s), 2.84 (1H, m), 3.19 (2H, d, J=3.9 Hz),3.96 (1H, d, m), 4.28 (1H, d, J=13.1 Hz), 5.21 (1H, d, J=13.1 Hz), 5.52(1H, s), 5.56 (1H, t, J=4.2 Hz), 7.25-7.59 (10H, m), 7.75 (2H, d, J=7.7Hz).

MS: m/z=475 [M+H]⁺.

Reference Example 142

According to Reference example 136, compound 142 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.10 (6H, m), 2.98 (3H, m), 3.78 (1H, m), 4.27 (1H,d, J=13.6 Hz), 4.68 (1H, m), 5.11 (1H, d, J=12.8 Hz), 5.51 (2H, m),7.07-7.46 (10H, m), 7.70 (2H, d, J=7.2 Hz).

MS: m/z=477 [M+H]⁺.

Reference Example 143

According to Reference example 136, compound 143 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.89 (3H, m), 3.62 (1H, m), 4.17 (1H, d, J=13.1 Hz),4.99 (1H, d, J=13.1 Hz), 5.45 (1H, s), 5.51 (1H, d, J=7.8 Hz), 7.18-7.77(17H, m).

MS: m/z=531 [M+H]⁺.

Reference Example 144

First Step

To compound 144A synthesized according to the first to fifth steps ofReference example 135 were added formic acid and formalin, and themixture was stirred at 80° C. for 1.5 hours. The solvent was distilledoff under reduced pressure, saturated sodium bicarbonate water wasadded, then the mixture was extracted with chloroform, and the extractwas dried with sodium sulfate. The solvent was concentrated underreduced pressure, and the resulting crude product was purified by silicagel column chromatography (chloroform-methanol, 95:5→92:8, v/v) toobtain 26 mg of compound 144B.

¹H-NMR (CDCl₃) δ: 2.06 (6H, s), 2.18-2.26 (1H, m), 2.36-2.45 (1H, m),2.89-2.98 (1H, m), 3.91 (1H, dt, J=14.1, 5.9 Hz), 4.43 (1H, d, J=13.6Hz), 4.82 (1H, d, J=13.4 Hz), 5.20 (1H, s), 5.41 (1H, d, J=10.8 Hz),5.46 (1H, d, J=10.7 Hz), 5.80 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=7.8 Hz),7.05-7.64 (15H, m).

Second Step

To compound 144B obtained in the first step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and an aqueous ammonium chloride solution, andthe mixture was extracted with chloroform, and dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 13 mg of compound 144 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.17 (6H, s), 2.38-2.46 (3H, m), 3.59 (1H, m), 4.41(1H, d, J=13.1 Hz), 5.09 (1H, d, J=13.3 Hz), 5.50 (1H, d, J=6.4 Hz),5.51 (1H, s), 7.19-7.47 (9H, m), 7.66 (2H, d, J=7.3 Hz).

MS: m/z=419 [M+H]⁺.

Reference Example 145

First Step

To a dichloromethane (5 ml) solution of compound 95E (300 mg, 0.664mmol) was added NBS (130 mg, 0.731 mmol) under ice-cooling, temperaturewas raised to room temperature and, thereafter, the mixture was refluxedfor 1 hour. After the solvent was distilled off, the resulting residuewas purified by silica gel chromatography. The materials were elutedfirstly with n-hexane-ethyl acetate (1:1, v/v) and, then, with ethylacetate. Concentration of an objective fraction afforded 326.7 mg (yield93%) of compound 145A as a solid.

¹H-NMR (CDCl₃) δ: 2.93 (3H, s), 4.27 (1H, d, J=13.5 Hz), 4.82 (1H, d,J=13.5 Hz), 5.13 (1H, s), 5.41 (2H, s), 5.41-7.12 (2H, m), 7.15 (1H, s),7.17-7.28 (3H, m), 7.31-7.47 (6H, m), 7.52 (2H, d, J=6.6 Hz), 7.63-7.67(2H, m).

Second Step

To a DMF (3 ml) solution of compound 145A (100 mg, 0.189 mmol) wereadded a solution of potassium carbonate (78.4 mg, 0.567 mmol) in water(0.5 ml), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane(47.6 mg, 0.284 mmol) and tetakistriphenylphosphinepalladium (21.8 mg,0.0189 mmol), and the mixture was heated to stir at 80° C. for 4 hours.After the reaction solution was cooled to room temperature, water wasadded, and the mixture was extracted with ethyl acetate three times. Theextract was washed with water three times, and dried with sodium sulfateand, thereafter, the resulting oil was purified by silica gelchromatography. Elution with only ethyl acetate, and concentration of anobjective fraction afforded 42.0 mg (yield 45%) of compound 145B as anoil.

¹H-NMR (CDCl₃) δ: 1.73 (3H, s), 2.92 (3H, s), 4.29 (1H, d, J=13.5 Hz),4.83 (1H, d, J=13.5 Hz), 4.96-4.97 (1H, m), 5.15 (1H, s), 5.21-5.21 (1H,m), 5.37 (1H, d, J=10.8 Hz), 5.40 (1H, d, J=10.8 Hz), 6.82 (1H, s),7.15-7.21 (5H, m), 7.27-7.47 (6H, m), 7.54 (2H, d, J=6.9 Hz), 7.64-7.69(2H, m).

Third Step

To a THF (2 ml) solution of compound 145B (40 mg, 0.081 mmol) was added10% Pd—C (8 mg), and the mixture was subjected to a catalytic reductionreaction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. The resulting residue was washed withether to obtain 6.8 mg (yield 21%) of compound 145.

¹H-NMR (CDCl₃) δ: 0.629 (3H, d, J=6.9 Hz), 0.900 (3H, d, J=6.9 Hz),2.87-3.00 (1H, m), 2.94 (3H, s), 4.37 (1H, d, J=13.2 Hz), 4.93 (1H, d,J=13.2 Hz), 5.21 (1H, s), 6.69 (1H, s), 7.21 (5H, s), 7.35-7.47 (3H, m),7.57 (2H, d, J=7.5 Hz).

Reference Example 146

According to Reference example 145, compound 146 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 0.738 (3H, t, J=7.2 Hz), 1.05-1.18 (2H, m), 2.01-2.18(2H, m), 2.94 (3H, s), 4.35 (1H, d, J=13.2 Hz), 4.95 (1H, d, J=13.2 Hz),5.22 (1H, s), 6.71 (1H, s), 7.20 (5H, s), 7.35-7.47 (3H, m), 7.55 (2H,d, J=6.9 Hz).

Reference Example 147

First Step

Compound 145A (60 mg, 0.113 mg) was dissolved in trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 30 mg (yield 60%) of compound 147.

¹H-NMR (CDCl₃) δ: 2.97 (3H, s), 4.36 (1H, d, J=13.2 Hz), 5.01 (1H, d,J=13.2 Hz), 5.21 (1H, s), 7.14 (1H, s), 7.17-7.25 (5H, m), 7.36-7.48(3H, m), 7.54 (2H, d, J=7.2 Hz).

Reference Example 148

Compound 145B (41 mg, 0.083 mg) was dissolved in trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 12 mg (yield 36%) of compound 148.

¹H-NMR (CDCl₃) δ: 1.70 (3H, s), 2.95 (3H, s), 4.36 (1H, d, J=12.9 Hz),4.95 (1H, d, J=12.9 Hz), 4.96-4.98 (1H, m), 5.23 (1H, s), 5.32-5.33 (1H,m), 6.86 (1H, s), 7.21 (5H, s), 7.35-7.48 (3H, m), 7.56 (2H, d, J=7.2Hz).

Reference Example 149

To a THF (2 ml) solution of compound 145A (100 mg, 0.189 mg) were addeda 2N methylzinc chloride THF solution (0.377 ml, 0.754 mmol) andtetrakistriphenylphosphinepalladium (10.9 mg, 0.0945 mmol) at roomtemperature, and the mixture was heated to stir at 60° C. for 4 hours.After the reaction solution was cooled to room temperature, water wasadded, and the mixture was extracted with chloroform three times. Afterthe extract was dried with sodium sulfate, the solvent was distilledoff, and the resulting oil was purified by a MS trigger reverse layercolumn to obtain 9.6 mg (yield 14%) of compound 149.

¹H-NMR (CDCl₃) δ: 1.63 (3H, s), 2.95 (3H, s), 4.34 (1H, d, J=12.9 Hz),4.68 (1H, d, J=12.9 Hz), 5.21 (1H, s), 6.70 (1H, s), 7.18 (5H, s),7.37-7.47 (3H, m), 7.54 (2H, d, J=6.9 Hz).

Reference Example 150

First Step

Reference compound 150A (465 mg, 0.801 mmol) synthesized according tothe first to fourth step of Reference example 135 was dissolved in a 4Nhydrochloric acid dioxane solution (5 ml), and the mixture was stirredat room temperature for 2 hours. The reaction solution was neutralizedwith saturated sodium bicarbonate water, and was extracted withdichloromethane three times. After the extract was dried with sodiumsulfate, the solvent was distilled off, and 100 mg of the resulting oilwas dissolved in dichloromethane (2 ml). To the dichloromethane solutionwere added triethylamine (63.2 mg, 0.624 mmol) and benzoyl chloride(31.9 mg, 0.312 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 1 hour. To the reaction solution was added water,and the mixture was extracted with dichloromethane three times. Afterthe extract was dried with sodium sulfate, the solvent was distilledoff, and the resulting residue was washed with diethyl ether to obtain68 mg (yield 56%) of compound 150B.

¹H-NMR (CDCl₃) δ: 3.05-3.12 (1H, m), 3.38-3.45 (1H, m), 3.64-3.70 (1H,m), 3.93-3.99 (1H, m), 4.22 (1H, d, J=13.2 Hz), 5.04 (1H, s), 5.07 (1H,d, J=13.2 Hz), 5.22 (1H, d, J=10.2 Hz), 5.31 (1H, d, J=10.2 Hz), 5.70(1H, d, J=7.8 Hz), 6.55 (1H, d, J=7.8 Hz), 6.98 (2H, d, J=6.6 Hz),7.08-7.19 (4H, m), 7.29-7.46 (5H, m), 7.49-7.53 (2H, m), 7.87 (2H, d,J=7.2 Hz), 8.06 (1H, brs).

Second Step

Compound 150B (30 mg, 0.051 mg) was dissolved in trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1 hour. Thesolvent was distilled off, the residue was dissolved in dichloromethane(2 ml), and the solution was neutralized with saturated sodiumbicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 15 mg (yield 59%) of compound 150.

¹H-NMR (CDCl₃) δ: 2.91-2.98 (1H, m), 3.54-3.66 (1H, m), 3.76-3.84 (1H,m), 4.13-4.18 (1H, m), 4.28 (1H, d, J=12.9 Hz), 5.11 (1H, s), 5.43 (1H,d, J=12.9 Hz), 5.45 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=7.5 Hz), 7.10-7.18(4H, m), 7.35-7.47 (8H, m), 7.89 (2H, d, J=7.2 Hz), 8.41 (1H, s).

Reference Example 151

According to Reference example 150, compound 151 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 2.69 (1H, brt, J=10.8 Hz), 3.40-3.49(1H, m), 3.06-3.74 (1H, m), 4.12-4.22 (1H, m), 4.20 (1H, d, J=12.9 Hz),5.08 (1H, s), 5.47 (1H, d, J=7.8 Hz), 5.50 (1H, d, J=12.9 Hz), 6.67 (1H,d, J=7.8 Hz), 7.12-7.21 (5H, m), 7.28-7.46 (5H, m), 8.31 (1H, brs).

Reference Example 152

First Step

Compound 150A (50 mg, 0.801 mmol) was dissolved in a 4N hydrochloricacid dioxane solution (5 ml), and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was neutralized withsaturated sodium bicarbonate water, and was extracted withdichloromethane three times. After the extract was dried with sodiumsulfate, the solvent was distilled off, and 50 mg of the resulting oilwas dissolved in methanol (2 ml). To the methanol solution was added 10%Pd—C (10 mg), and the mixture was subjected to a catalytic reductionreaction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 10mg (yield 25%) of compound 152.

¹H-NMR (DMSO-d₆) δ: 2.74-2.78 (2H, m), 3.00-3.07 (1H, m), 3.78-3.85 (1H,m), 4.34 (1H, d, J=13.5 Hz), 5.13 (1H, d, J=13.5 Hz), 5.48-5.54 (1H, m),5.10 (1H, s), 7.20-7.47 (9H, m), 7.63-7.71 (2H, m).

Reference Example 153

First Step

To a THF (3 ml) solution of compound 150A (30 mg, 0.052 mmol) was added10% Pd—C (10 mg), and the mixture was subjected to a catalytic reductionreaction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 20mg (yield 79%) of compound 153.

¹H-NMR (CDCl₃) δ: 1.34 (9H, s), 2.84-2.91 (1H, m), 3.18-3.25 (2H, m),4.03-4.11 (1H, m), 4.35 (1H, d, J-=13.2 Hz), 5.20 (1H, s), 5.24 (1H, d,J=13.2 Hz), 5.49 (1H, brs), 5.70 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.8Hz), 7.16-7.20 (5H, m), 7.32-7.46 (3H, m), 7.53 (2H, d, J=7.2 Hz).

Reference Example 154

First Step

To a DMF (10 ml) solution of compound 154A (539 mg, 1.01 mmol)synthesized according to the synthesis method of Reference example 65were added triethylamine (615.7 mg, 6.08 mmol) and ethyl chlorocarbonate(328.8 mg, 3.03 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 10 minutes. To the reaction solution were addedO,N-dimethylhydroxylamine hydrochloride (295.0 mg, 3.03 mmol) and DMAP(12.3 mg, 0.101 mmol), the mixture was stirred at the same temperaturefor 2 hours, water was added, and was extracted with ethyl acetate threetimes. After the extract was washed with water three times, and driedwith sodium sulfate, the solvent was distilled off, and the resultingoil was purified by silica gel chromatography. The materials were elutedfirstly with n-hexane-ethyl acetate (7:3, v/v) and, then, with onlyethyl acetate. Concentration of an objective fraction afforded 445.4 mg(yield 76%) of compound 154B as an oil.

¹H-NMR (DMSO-d₆) δ: 3.09 (3H, s), 3.52 (3H, s), 3.94 (2H, s), 4.40 (1H,brs), 4.64 (2H, s), 4.96 (1H, brs), 5.15 (2H, s), 7.06-7.15 (4H, m),7.21 (2H, t, J=8.7 Hz), 7.28-7.38 (3H, m), 7.43 (2H, dd, J=5.7 Hz, 8.4Hz), 7.52-7.54 (2H, m), 7.66 (1H, s).

Second Step

A THF (5 ml) solution of compound 154B (250 mg, 0.435 mmol) was cooledto −78° C., a methylmagnesium bromide 0.97M THF solution (0.673 ml,0.653 mmol) was added, and temperature was raised to −20° C. over 2hours. To the reaction solution was added 1N hydrochloric acid, and themixture was extracted with ethyl acetate three times. After the extractwas dried with sodium sulfate, the solvent was distilled off, and theresulting oil was purified by silica gel chromatography. The materialswere eluted firstly with only chloroform and, then, withchloroform-methanol (7:3, v/v). Concentration of an objective fractionafforded 117.0 mg (yield 51%) of compound 154C as an oil.

¹H-NMR (CDCl₃) δ: 2.68 (3H, s), 3.80 (2H, brs), 4.29 (2H, brs), 4.71(2H, brs), 5.45 (2H, brs), 6.83 (2H, m), 6.92-6.98 (2H, m), 7.03-7.10(2H, m), 7.28-7.39 (5H, m), 7.90 (1H, s).

Third Step

To a dichloromethane (2 ml) solution of compound 154C (117 mg, 0.221mmol) was added mCPBA (52.7 mg, 0.332 mmol) under ice-cooling, and themixture was stirred at room temperature for 2 hours. To the reactionsolution was added an aqueous sodium thiosulfate solution, and themixture was extracted with ethyl acetate three times. After the extractwas washed with saturated sodium bicarbonate water two times, and driedwith sodium sulfate, the solvent was distilled off, the resulting oilwas dissolved in ethanol (2 ml), and the solution was refluxed for 1hour. After the solvent was distilled off, the precipitated solid waswashed with diisopropyl ether to obtain 54 mg (yield 49%) of compound154D.

¹H-NMR (CDCl₃) δ: 3.74 (1H, brs), 3.85 (1H, brs), 4.20 (2H, brs), 4.61(1H, brs), 4.93 (1H, brs), 5.41 (2H, brs), 6.79-6.86 (2H, m), 6.91-6.96(2H, m), 7.02-7.09 (2H, m), 7.15-7.16 (1H, m), 7.26-7.34 (5H, m),7.56-7.65 (2H, m).

Fourth Step

To a THF (3 ml) solution of compound 154D (54 mg, 0.107 mmol) was added10% Pd—C (20 mg), and the mixture was subjected to a catalytic reductionreaction under hydrogen stream. The catalyst was removed by filtration,and the filtrate was concentrated. To the resulting residue was addeddiisopropyl ether, and the precipitated solid was filtered to obtain 21mg (yield 47%) of compound 154.

¹H-NMR (DMSO-d₆) δ: 3.90 (2H, brs), 3.95 (2H, s), 4.66 (2H, brs),7.07-7.12 (4H, m), 7.22 (2H, t, J=8.7 Hz), 7.29 (1H, s), 7.43-7.47 (2H,m).

Reference Example 155

First Step

To a toluene (150 mL) solution of compound 155A (WO 2006/066414, 15.0 g,38.4 mmol) were sequentially added N,N-diisopropylethylamine (16.1 mL,92.0 mmol), 1-methylimidazole (3.70 mL, 46.4 mmol) and2-methoxyethylamine (4.05 mL, 46.4 mmol) under ice-cooling and,thereafter, diphenyl chlorophosphate (9.60 mL, 46.1 mmol) was furtheradded dropwise over 10 minutes. After the reaction solution was stirredfor 20 minutes under ice-cooling, acetonitrile (50 mL) was added, andthe mixture was further stirred for 2 hours. To the reaction solutionwas added an aqueous acetic acid solution (10%, 100 mL) underice-cooling and, thereafter, the mixture was extracted with ethylacetate. The extract was sequentially washed with water (100 mL),saturated sodium bicarbonate water (150 mL) and an aqueous saturatedsodium chloride solution (100 mL) and, thereafter, dried with sodiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel column chromatography(ethyl acetate/n-hexane=25% 50%) to obtain compound 155B (7.86 g, 46%)as a colorless oil.

¹H-NMR (CDCl₃) δ: 0.10 (6H, s), 0.93 (9H, s), 3.29 (3H, s), 3.39 (2H,m), 3.47 (2H, m), 4.56 (2H, d, J=1.2 Hz), 5.41 (2H, s), 6.60 (1H, s),7.35-7.42 (5H, m), 8.11 (1H, brt).

Second Step

To an ethanol (80 mL) solution of compound 155B (7.70 g, 17.2 mmol) wasadded aqueous ammonia (40 mL) at room temperature, and the mixture wasstirred for 18 hours. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=75%→100%) to obtain compound 155C(7.15 g, 93%) as a colorless oil.

¹H-NMR (CDCl₃) δ: 0.14 (6H, s), 0.97 (9H, s), 3.28 (3H, s), 3.38 (2H,m), 3.49 (2H, m), 4.64 (2H, s), 5.53 (2H, s), 6.31 (1H, s), 7.34-7.49(5H, m), 8.61 (1H, brs), 9.94 (1H, brs).

Third Step

To a DMF (125 mL) solution of compound 155C (7.15 g, 16.0 mmol) andpotassium carbonate (6.64 g, 48.0 mmol) was addedO-(2,4-dinitrophenyl)hydroxylamine (7.97 g, 40.0 mmol) at roomtemperature, and the mixture was stirred for 2 days. To the reactionsolution was added water (250 mL) under ice-cooling and, thereafter, themixture was extracted with ethyl acetate (300 mL×2). After the extractwas sequentially washed with water (300 mL), saturated sodiumbicarbonate water (300 mL×2) and an aqueous saturated sodium chloridesolution (150 mL), the mixture was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel column chromatography(methanol/chloroform=0%→10%) to obtain compound 155D (6.47 g, 88%) as apale yellow solid.

¹H-NMR (CDCl₃) δ: 0.11 (6H, s), 0.94 (9H, s), 3.26 (3H, s), 3.35 (4H,m), 4.66 (2H, s), 5.16 (2H, s), 5.24 (2H, s), 6.43 (1H, s), 7.31-7.40(5H, m), 7.59 (1H, brs).

Fourth Step

To a toluene (100 mL) solution of compound 155D (6.47 g, 14.0 mmol) andacetic acid (0.080 mL, 1.4 mmol) was added paraformaldehyde (0.422 g,14.1 mmol) at room temperature, and the mixture was stirred at 80° C.for 2 hours. The solvent was distilled off under reduced pressure, andthe resulting crude product of compound 155E was utilized in a next stepwithout purification.

Fifth Step

To a DMF (100 mL) solution of the crude product of compound 155Eobtained in the fourth step was added cesium carbonate (22.7 g, 69.8mmol) under ice-cooling, and the mixture was stirred for 1 hour. Underice-cooling, bromodiphenylmethane (5.20 g, 21.0 mmol) was added, and themixture was stirred at room temperature for 19 hours. To the reactionsolution was added water (200 mL) under ice-cooling and, thereafter, themixture was extracted with ethyl acetate (200 mL×3). The extract wassequentially washed with water (200 mL×2) and an aqueous saturatedsodium chloride solution (100 mL), and dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingcrude product of compound 155F was utilized in a next step withoutpurification.

MS: m/z=640 [M+H]⁺.

Sixth Step

To a methanol (100 mL) solution of the crude product of compound 155Fobtained in the fifth step was added hydrogen chloride (4N ethyl acetatesolution, 40 mL) at room temperature, and the mixture was stirred for2.5 hours. To the reaction solution was added an aqueous sodiumhydroxide solution (2N, 75 mL) to perform neutralization (pH=6) underice-cooling, and the mixture was extracted with chloroform (200 mL×3).The extract was dried with sodium sulfate, the solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (methanol/chloroform=5%→40%) to obtaincompound 155G (5.18 g, 3 step 70%) as an orange oil.

¹H-NMR (CDCl₃) δ: 3.16 (3H, s), 3.18-3.43 (3H, m), 3.60-3.74 (2H, m),4.06 (1H, d, J=13.5 Hz), 4.19 (1H, brs), 4.58 (1H, d, J=14.7 Hz), 5.00(1H, d, J=13.5 Hz), 5.24 (1H, s), 5.27 (2H, s), 5.96 (1H, s), 6.78 (2H,m), 6.98-7.10 (3H, m), 7.30-7.42 (8H, m), 7.72 (2H, m).

Seventh Step

To a THF (2 mL) solution of compound 155G (100 mg, 0.190 mmol),(bromomethyl)cyclopropane (0.110 mL, 1.12 mmol) and sodium iodide (5.0mg, 0.033 mmol) was added potassium tert-butoxide (78.0 mg, 0.695 mmol)at room temperature, the mixture was stirred at room temperature for 22hours and, thereafter, the mixture was stirred at 100° C. for 10 minutesunder microwave irradiation. To the reaction solution were added waterand hydrochloric acid (2N) (pH=1), the mixture was extracted withchloroform, and the extract was dried with sodium sulfate. The solventwas distilled off under reduced pressure, and the resulting crudeproduct of compound 155H was utilized in a next step withoutpurification.

MS: m/z=580 [M+H]⁺.

Eighth Step

To a DMF (2 mL) solution of the crude product of compound 155H obtainedin the seventh step was added lithium chloride (35.0 mg, 0.826 mmol) atroom temperature, and the mixture was stirred at 150° C. for 15 minutesunder microwave irradiation. The reaction solution was purified bypreparative LCMS to obtain compound 155 (4.3 mg, 2 step 5%) as a whitesolid.

¹H-NMR (CDCl₃) δ: 0.16 (2H, m), 0.52 (2H, m), 0.98 (1H, m), 3.08 (3H,m), 3.20 (3H, s), 3.46 (2H, m), 3.68 (1H, dd, J=0.6, 14.1 Hz), 3.90 (1H,m), 4.52 (1H, d, J=13.2 Hz), 4.58 (1H, d, J=14.1 Hz), 4.93 (1H, d,J=13.2 Hz), 5.38 (1H, s), 6.01 (1H, s), 6.98 (2H, m), 7.11-7.48 (8H, m).

MS: m/z=490 [M+H]⁺.

Reference Example 156

According to Reference example 155, compound 156 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=7.4 Hz), 1.51 (2H, m), 3.15-3.23 (6H,m), 3.46 (2H, m), 3.69 (1H, dd, J=0.6, 14.1 Hz), 3.88 (1H, m), 4.54 (2H,d, J=14.1 Hz), 4.58 (1H, d, J=14.1 Hz), 4.93 (1H, d, J=13.5 Hz), 5.39(1H, s), 6.12 (1H, s), 6.97 (2H, m), 7.12-7.47 (8H, m).

MS: m/z=478 [M+H]⁺.

Reference Example 157

According to Reference example 155, compound 157 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 3.13-3.22 (1H, m), 3.18 (3H, s), 3.20 (3H, s),3.41-3.51 (2H, m), 3.60 (1H, d, J=13.8 Hz), 3.89 (1H, ddd, J=3.3 Hz, 4.2Hz, 14.4 Hz), 4.52 (1H, d, J=13.2 Hz), 4.53 (1H, d, J=13.8 Hz), 4.92(1H, d, J=13.2 Hz), 5.38 (1H, s), 5.98 (1H, s), 6.98 (2H, d, J=8.4 Hz),7.11-7.22 (3H, m), 7.36-7.48 (5H, m).

Reference Example 158

First Step

To a THF (100 mL) solution of compound 155G (960 mg, 1.83 mmol) wasadded manganese dioxide (2.06 g, 92.0 mmol) at room temperature, and themixture was stirred for 2 days. After the reaction solution wasfiltered, the filtrate was distilled off under reduced pressure, and theresulting residue was purified by silica gel column chromatography(ethyl acetate/n-hexane=60%→100%) to obtain compound 158A (554 mg, 58%)as a pale yellow foam.

¹H-NMR (CDCl₃) δ: 2.96 (1H, m), 3.18 (3H, s), 3.44 (2H, m), 4.18 (1H,m), 4.56 (1H, d, J=13.8 Hz), 4.98 (1H, d, J=13.8 Hz), 5.28 (1H, s), 5.54(1H, d, J=10.5 Hz), 5.64 (1H, d, J=10.5 Hz), 6.35 (1H, s), 6.85 (2H, m),7.03 (2H, m), 7.18 (1H, m), 7.26-7.48 (8H, m), 7.64 (2H, m), 10.10 (1H,s).

Second Step

To a methylene chloride (4 mL) solution of compound 158A (83.0 mg, 0.159mmol), pyrrolidine (0.0400 mL, 0.484 mmol) and acetic acid (0.100 mL)was added sodium triacetoxyborohydride (136 mg, 0.642 mmol) at roomtemperature, and the mixture was stirred for 28 hours. To the reactionsolution was added water, the mixture was extracted with chloroform, andthe extract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting crude product of compound 158Bwas utilized in a next step without purification.

MS: m/z=579 [M+H]⁺.

Third Step

To a DMF (2 mL) solution of the crude product of compound 158B obtainedin the second step was added lithium chloride (39.2 mg, 0.925 mmol) atroom temperature, and the mixture was stirred at 150° C. for 15 minutesunder microwave irradiation. The reaction solution was distilled offunder reduced pressure, and the resulting residue was purified bypreparative LCMS to obtain compound 158 (8.8 mg, 2 step 11%) as a yellowoil.

¹H-NMR (CDCl₃) δ: 1.84 (4H, m), 2.70-2.85 (5H, m), 3.19 (3H, s),3.20-3.47 (3H, m), 3.80 (1H, m), 4.25 (1H, d, J=14.7 Hz), 4.57 (1H, d,J=13.5 Hz), 5.07 (1H, d, J=13.5 Hz), 5.39 (1H, s), 6.06 (1H, s), 6.97(2H, m), 7.12-7.54 (8H, m), 8.29 (1H, s).

MS: m/z=489 [M+H]⁺.

Reference Example 159

First Step

To a methylene chloride (20 mL) solution of compound 155G (950 mg, 1.81mmol) and N,N-diisopropylethylamine (0.380 mL, 2.18 mmol) was addeddropwise methanesulfonyl chloride (0.148 mL, 1.90 mmol) underice-cooling, and the mixture was stirred for 90 minutes. To the reactionsolution was added water (20 mL), the mixture was extracted withchloroform (50 mL), and the extract was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingcrude product (1.06 g) of compound 159A was utilized in a next stepwithout purification.

MS: m/z=604 [M+H]⁺.

Second Step

To the crude product (161 mg) of compound 159A obtained in the firststep was added dimethylamine (2M THF solution, 2.00 mL, 4.00 mmol) atroom temperature, and the mixture was stirred for 3 days. To thereaction solution was added an aqueous saturated sodium chloridesolution (2 mL), the mixture was extracted with ethyl acetate, and theextract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting crude product of compound 159Bwas utilized in a next step without purification.

MS: m/z=553 [M+H]⁺.

Third Step

To a DMF (2 mL) solution of the crude product of compound 159B obtainedin the second step was added lithium chloride (56.0 mg, 1.32 mmol) atroom temperature, and the mixture was stirred at 150° C. for 30 minutesunder microwave irradiation. The reaction solution was distilled offunder reduced pressure, and the resulting residue was purified bypreparative LCMS to obtain compound 159 (33.6 mg, 3 step 27%) as a whitesolid.

¹H-NMR (CDCl₃) δ: 2.37 (6H, s), 2.69 (1H, d, J=14.4 Hz), 3.19 (3H, s),3.30-3.46 (3H, m), 3.76 (1H, m), 4.00 (1H, d, J=14.4 Hz), 4.60 (1H, d,J=13.5 Hz), 5.20 (1H, d, J=13.5 Hz), 5.40 (1H, s), 6.01 (1H, s), 6.97(2H, m), 7.11-7.42 (8H, m).

MS: m/z=463 [M+H]⁺.

Reference Example 160

First Step

To a crude product (95.8 mg) of compound 159A was added methylamine (2MTHF solution, 2.00 mL, 4.00 mmol) at room temperature, and the mixturewas stirred for 3 days. The reaction solution was filtered, the solventwas distilled off under reduced pressure, and the resulting crudeproduct of compound 160A was utilized in a next step withoutpurification.

MS: m/z=539 [M+H]⁺.

Second Step

To an acetonitrile (3 mL) suspension of the crude product of compound160A and sodium iodide (100 mg, 0.667 mmol) was addedchlorotrimethylsilane (0.0850 mL, 0.665 mmol) at room temperature, andthe mixture was stirred for 5 hours. To the reaction solution was addedwater (1 mL), the solvent was distilled off under reduced pressure, andthe resulting residue was purified by preparative LCMS to obtaincompound 160 (59.8 mg, 3 step 84%) as a white solid.

¹H-NMR (CDCl₃) δ: 2.75 (3H, s), 3.08 (1H, d, J=13.5 Hz), 3.24 (3H, s),3.30-3.40 (3H, m), 3.75 (1H, m), 4.32 (1H, d, J=13.8 Hz), 4.66 (1H, d,J=13.8 Hz), 5.33 (1H, s), 5.58 (1H, d, J=13.5 Hz), 6.40 (1H, s), 6.98(2H, m), 7.12-7.25 (3H, m), 7.40-7.51 (2H, m), 7.60 (2H, m).

MS: m/z=449 [M+H]⁺.

Reference Example 161

First Step

After a DMF (2 mL) suspension of a crude product (156 mg) of compound159A, imidazole (19.5 mg, 0.286 mmol) and potassium carbonate (37.7 mg,0.273 mmol) was stirred at room temperature for 4 hours, sodium hydride(60%, 11.7 mg, 0.293 mmol) was added, and the mixture was stirred for 3days. To the reaction solution was added an aqueous acetic acid solution(10%), the mixture was extracted with chloroform, and the extract wasdried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting crude product of compound 161A was utilizedin a next step without purification.

MS: m/z=576 [M+H]⁺.

Second Step

To the crude product of compound 161A was added trifluoroacetic acid (1mL) at room temperature, and the mixture was stirred for 18 hours and,thereafter, the mixture was stirred at 60° C. for 3 hours. The reactionsolution was distilled off under reduced pressure, and the resultingresidue was purified by preparative LCMS to obtain compound 161 (19.8mg, 3 step 16%) as a pale orange amorphous substance.

¹H-NMR (CDCl₃) δ: 3.17-3.25 (1H, m), 3.21 (3H, s), 3.38-3.47 (2H, m),3.82 (1H, m), 4.40 (1H, d, J=16.5 Hz), 4.54 (1H, d, J=13.5 Hz), 5.02(1H, d, J=13.5 Hz), 5.09 (1H, s), 5.32 (1H, d, J=16.5 Hz), 5.40 (1H, s),6.65 (1H, brs), 7.03 (2H, m), 7.15-7.49 (8H, m), 8.08 (1H, brs).

MS: m/z=486 [M+H]⁺.

Reference Example 162

First Step

To a DMF (2 mL) solution of a crude product (192 mg) of compound 159Awas added sodium azide (24.2 mg, 0.372 mmol) at room temperature, andthe mixture was stirred at 60° C. for 2 hours. The reaction solution wasdistilled off under reduced pressure, and the resulting crude product ofcompound 162A was utilized in a next step without purification.

MS: m/z=551 [M+H]⁺.

Second Step

To a THF (4 mL) solution of the crude product of compound 162A weresequentially added water (0.200 mL) and triphenylphosphine (83.0 mg,0.316 mmol) at room temperature, and the mixture was stirred at 60° C.for 1 hour. The reaction solution was distilled off under reducedpressure, and the resulting residue was purified by preparative LCMS toobtain compound 162B (110 mg, 3 step 66%) as a colorless oil.

MS: m/z=525 [M+H]⁺.

Third Step

To an acetonitrile (1 mL) suspension of compound 162B (50.0 mg, 0.0950mmol) and sodium iodide (56.2 mg, 0.375 mmol) was addedchlorotrimethylsilane (0.0490 mL, 0.381 mmol) at room temperature, andthe mixture was stirred for 6 hours. To the reaction solution was addedwater (0.5 mL), the solvent was distilled off under reduced pressure,and the resulting residue was purified by preparative LCMS to obtaincompound 162 (25.9 mg, 63%) as a pale orange solid.

¹H-NMR (CDCl₃) δ: 3.12 (1H, d, J=14.7 Hz), 3.27 (3H, s), 3.35-3.48 (3H,m), 3.81 (1H, m), 4.65 (1H, d, J=13.5 Hz), 5.31 (1H, s), 5.59 (1H, d,J=13.5 Hz), 6.40 (1H, s), 6.98 (2H, m), 7.19 (3H, m), 7.40 (1H, m), 7.50(2H, m), 7.62 (2H, m), 8.11 (1H, s).

MS: m/z=435 [M+H]⁺.

Reference Example 163

First Step

To an acetonitrile (3 mL) solution of compound 162B (50.0 mg, 0.0950mmol) and N,N-diisopropylethylamine (0.0366 mL, 0.210 mmol) was addedacetic anhydride (0.0100 mL, 0.106 mmol) at room temperature, and themixture was stirred for 6 hours. The reaction solution was distilled offunder reduced pressure, and the resulting crude product of compound 163Awas utilized in a next step without purification.

MS: m/z=567 [M+H]⁺.

Second Step

To an acetonitrile (5 mL) suspension of the crude product of compound163A and sodium iodide (59.2 mg, 0.395 mmol) was addedchlorotrimethylsilane (0.0487 mL, 0.381 mmol) at room temperature, andthe mixture was stirred for 16 hours. To the reaction solution was addedwater (0.5 mL), the solvent was distilled off under reduced pressure,and the resulting residue was purified by preparative LCMS to obtaincompound 163 (28.1 mg, 2 step 62%) as a pale orange foam.

¹H-NMR (CDCl₃) δ: 2.07 (3H, s), 3.24 (3H, s), 3.27-3.52 (4H, m), 3.67(1H, m), 4.54 (1H, d, J=13.5 Hz), 4.78 (1H, dd, J=6.5, 14.9 Hz), 5.17(1H, d, J=13.5 Hz), 5.28 (1H, s), 5.61 (1H, s), 7.01 (2H, m), 7.01-7.58(9H, m).

MS: m/z=477 [M+H]⁺.

Reference Example 164

First Step

Compound 155G (43.3 mg, 0.221 mmol) was dissolved in trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.The solvent was distilled off, the residue was dissolved indichloromethane (2 ml), and the solution was neutralized with saturatedsodium bicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 22 mg (yield 61%) of compound 164.

¹H-NMR (CDCl₃) δ: 1.13 (6H, d, J=6.0 Hz), 3.18-3.77 (7H, m), 3.26 (3H,s), 4.49 (1H, d, J=12.3 Hz), 4.76 (1H, d, J=12.3 Hz), 5.27 (2H, brs),5.89 (1H, s), 6.90 (2H, d, J=7.2 Hz), 6.98-7.14 (3H, m), 7.315-7.50 (5H,m).

Reference Example 165

First Step

To a DMF (370 mL) solution of compound 165A (WO 2006/088173, 37.0 g, 108mmol) were sequentially added potassium carbonate (17.9 g, 129 mmol) andmethyl iodide (8.03 mL, 129 mmol) at room temperature, and the mixturewas stirred for 1.5 hours. The reaction solution was added to a solutionof ammonium chloride (20.8 g, 390 mmol) in water (1110 mL) underice-cooling, and the precipitated solid was filtered, and washed withwater to obtain a crude product (33 g). In addition, the aqueous layerwas salted out with sodium chloride, and the mixture was extracted withethyl acetate, and dried with sodium sulfate. The solvent was distilledoff under reduced pressure, and a crude product (9 g) was obtained fromthe resulting residue. The crude products were combined and purified bysilica gel column chromatography (ethyl acetate/n-hexane=50%→100%) toobtain compound 165B (36.5 g, 95%) as a white solid.

Second Step

To a 1,4-dioxane (548 mL) solution of compound 165B (36.5 g, 102 mmol)were sequentially added potassium osmate dihydrate (1.13 g, 3.06 mmol),sodium periodate (87.3 g, 408 mmol) and water (365 mmol) at roomtemperature, and the mixture was stirred for 6 hours. The reactionsolution was extracted with methylene chloride, and the extract wasdried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=50%→100%) to obtain compound 165C(33.0 g, 90%) as a bronzed foam.

Third Step

To a toluene (25 mL) suspension of compound 165C (1.38 g, 3.66 mmol)were sequentially added ethylenediamine (0.247 mL, 3.66 mmol) and aceticacid (0.0210 mL, 0.366 mmol) at room temperature and, thereafter, themixture was stirred for 1 hour, and further stirred at 50° C. for 17hours. The precipitated solid was filtered, and washed with ether toobtain compound 165D (1.11 g, 100%) as a pale yellow solid.

¹HNMR (DMSO-d₆) δ: 3.05 (2H, m), 3.26 (1H, m), 3.63 (2H, m), 3.75 (3H,s), 3.87 (1H, m), 4.52 (1H, dd, J=3.3, 12.6 Hz), 4.69 (1H, m), 4.99 (1H,d, J=10.4 Hz), 5.15 (1H, d, J=10.4 Hz), 7.35 (3H, m), 7.54 (2H, m), 8.41(1H, s).

Fourth Step

To an acetonitrile (30 mL) suspension of compound 165D (2.77 g, 7.50mmol), potassium carbonate (2.23 g, 16.1 mmol) and sodium iodide (102mg, 0.680 mmol) was added bromodiphenylmethane (2.26 g, 9.14 mmol) atroom temperature, and the mixture was stirred at 90° C. for 7 hours. Thereaction solution was poured into hydrochloric acid (2N, 10 mL) and anice (20 g), the mixture was extracted with chloroform (100 mL×2), andthe extract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (chloroform/methanol=0% 5%) to obtain compound165E (2.72 g, 68%) as a pale yellow solid.

Fifth Step

To an ethanol (30 mL) solution of compound 165E (2.72 g, 5.08 mmol) wasadded an aqueous sodium hydroxide solution (2N, 10 mL) at roomtemperature, and the mixture was stirred for 3 days. To the reactionsolution was added hydrochloric acid (1N, 20 mL) (pH=1) at roomtemperature, the mixture was extracted with chloroform (100 mL×2), andthe extract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (chloroform/methanol=0%→10%) to obtaincompound 165F (1.77 g, 67%) as a pale yellow solid.

¹HNMR (DMSO-d₆) δ: 2.63 (1H, m), 3.16 (1H, m), 3.49 (1H, m), 3.73 (1H,m), 4.12 (2H, m), 4.56 (1H, m), 5.04 (1H, s), 5.09 (1H, d, J=10.7 Hz),5.19 (1H, d, J=10.7 Hz), 7.28-7.53 (15H, m), 8.32 (1H, s), 8.39 (1H, s).

Sixth Step

A N,N′-dimethylimidazolidinone (20 mL) solution of compound 165F (1.77g, 3.39 mmol) and lithium chloride (0.515 g, 12.2 mmol) was stirred at90° C. for 1 hour. To the reaction solution were sequentially addedwater (10 mL), hydrochloric acid (2N, 10 mL) and water (10 mL) at roomtemperature. The precipitated solid was filtered, and washed with ether,DMF-water were added, and the precipitated solid was filtered to obtaincompound 165 (599 mg, 41%) as a white solid.

¹HNMR (DMSO-d₆) δ: 2.60 (1H, m), 3.20 (1H, m), 3.64 (2H, m), 4.00 (2H,m), 4.55 (1H, m), 5.01 (1H, s), 7.28-7.47 (10H, m), 8.16 (1H, s), 11.97(1H, brs).

MS: m/z=432 [M+H]⁺.

Reference Example 166

According to Reference example 165, following compound 166 wassynthesized by the same procedure.

¹HNMR (DMSO-d₆) δ: 1.54 (1H, d, J=12.6H), 1.66-1.78 (1H, m), 2.60 (1H,t, J=9.9 Hz), 2.83 (1H, d, J=11.7 Hz), 3.01 (1H, t, J=11.7 Hz),3.34-3.38 (1H, m), 3.94 (1H, d, J=13.8 Hz), 4.44-4.59 (3H, m), 4.82 (1H,d, J=14.7 Hz), 7.06 (2H, t, J=8.7 Hz), 7.18-7.23 (2H, m), 8.27 (1H, s),12.84 (1H, brs).

Reference Example 167

First Step

To a xylene (30 ml) solution of compound 167A (WO 2006/11674, 3.58 g,7.61 mmol) were added (S)—N1-benzyl-3-phenylpropane-1,2-diamine (Journalof the American Chemical Society; English; 127; 30; 2005; 10504, 1.83 g,7.61 mmol) and acetic acid (0.5 ml), and the mixture was refluxed for 2hours. After cooling to room temperature, the solvent was distilled off,and the resulting oil was purified by silica gel chromatography. Thematerials were eluted firstly with n-hexane-ethyl acetate (9:1, v/v)and, then, with n-hexane-ethyl acetate (1:1, v/v). Concentration of anobjective fraction afforded 349 mg (yield 7%) of compound 167B as anoil.

¹HNMR (CDCl₃) δ: 2.54 (1H, t, J=9.6 Hz), 2.77 (1H, dd, J=9.0 Hz, 13.2Hz), 3.31 (1H, dd, J=6.9 Hz, 9.6 Hz), 3.43-3.78 (5H, m), 4.04-4.15 (1H,m), 4.42-4.48 (1H, m), 4.62 (2H, d, J=6.0 Hz), 5.29 (1H, d, J=10.5 Hz),5.43 (1H, d, J=10.5 Hz), 6.77-6.85 (2H, m), 7.19-7.39 (14H, m), 7.60(2H, d, J=6.3 Hz), 8.05 (1H, s).

Second Step

To a MeCN (10 ml) solution of compound 167B (968 mg, 1.47 mmol) wereadded Boc2O (3 ml) and DMAP (180 mg, 1.47 mmol), and the mixture washeated to reflux for 5 hours. To the reaction solution was added a 2Naqueous sodium hydroxide solution to stop the reaction, the reactionsolution was neutralized using 2N hydrochloric acid and, thereafter, themixture was extracted with ethyl acetate three times. After the extractwas washed with an aqueous saturated sodium chloride solution, thesolvent was distilled off, and the resulting oil was purified by silicagel chromatography. The materials were eluted firstly withn-hexane-ethyl acetate (6:4, v/v) and, then, only with ethyl acetate.Concentration of an objective fraction afforded 349 mg (yield 45%) ofcompound 167C.

¹HNMR (CDCl₃) δ: 2.54 (1H, t=9.0 Hz), 2.76 (1H, dd, J=9.3 Hz, 16.5 Hz),3.31 (1H, dd, J=6.9 Hz, 9.6 Hz), 3.45 (1H, dd, J=3.3 Hz, 12.6 Hz),3.51-3.78 (4H, m), 4.04-4.13 (1H, m), 4.42-4.52 (1H, m), 4.61 (2H, d,J=6.0 Hz), 2.79 (1H, d, J=10.2 Hz), 5.29 (1H, d, J=10.2 Hz), 5.43 (1H,d, J=10.2 Hz), 6.76-7.39 (11H, m), 7.60 (2H, d, J=6.6 Hz), 8.05 (1H, s),10.42 (1H, t, J=5.7 Hz).

Third Step

The compound 167C (150 mg, 0.280 mmol) was dissolved in trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.The solvent was distilled off, the residue was dissolved indichloromethane (2 ml), and the solution was neutralized with saturatedsodium bicarbonate water. The resulting solution was made acidic with anaqueous citric acid solution, and the organic layer was separated. Theaqueous layer was extracted with dichloromethane once, and the combinedorganic layers were washed with water, and dried with sodium sulfate.After the solvent was distilled off, the resulting solid was washed withdiisopropyl ether to obtain 71 mg (yield 57%) of compound 167.

¹HNMR (CDCl₃) δ: 2.65 (1H, dd, J=8.4 Hz, 9.6 Hz), 2.97 (1H, dd, J=9 Hz,13.5 Hz), 3.43 (1J, dd, J=7.2 Hz, 9.6 Hz), 3.55 (1H, dd, J=3.0 Hz, 13.2Hz), 3.61-3.80 (4H, m), 4.15 (1H, dd, J=4.2 Hz, 9.9 Hz), 4.51-4.60 (1H,m), 7.15-7.18 (2H, m), 7.28-7.38 (8H, m), 8.02 (1H, s), 12.04 (1H, s).

Reference Example 168

First Step

To a DMF (3 mL) solution of compound 168A (WO 2006/116764, 400 mg, 0.840mmol) were added cesium carbonate (821 mg, 2.52 mmol) and, subsequently,bromomethylenedibenzene (311 mg, 1.26 mmol), and the mixture was stirredat 100° C. for 5 hours. To the reaction solution were added 2N aqueoushydrochloric acid solution, water and ethyl acetate, the ethyl acetatelayer was separated, and the aqueous layer was extracted with ethylacetate once. The combined extracts were washed with an aqueoussaturated sodium bicarbonate solution and brine, dried with magnesiumsulfate, filtered and concentrated. The resulting residue was purifiedby silica gel column chromatography. Concentration of an objectivefraction afforded 100 mg of compound 168B as a yellow oil.

¹H-NMR (CDCl₃) δ: 1.79-1.84 (2H, m), 2.67-2.77 (1H, m), 2.84-3.05 (2H,m), 4.03 (1H, dd, J=13.0, 4.2 Hz), 4.28 (1H, dd, J=13.6, 6.5 Hz), 4.49(1H, dd, J=6.4, 3.8 Hz), 4.57 (2H, d, J=5.7 Hz), 4.78 (1H, dd, J=13.4,5.7 Hz), 4.93 (1H, s), 5.27 (2H, s), 7.00 (2H, t, J=8.8 Hz), 7.15-7.37(14H, m), 7.57-7.63 (2H, m), 7.76 (1H, s), 10.44 (1H, t, J=5.9 Hz).

MS: m/z=643.20 [M+H]⁺.

Second Step

Compound 168B (100 mg, 0.156 mmol) was dissolved in acetonitrile (3 mL),Boc2O (4.0 mL, 17.3 mmol) and, subsequently, DMAP (84 mg, 0.69 mmol)were added, and the mixture was stirred at 80° C. for 6 hours. Thereaction solution was allowed to cool, a 2N aqueous sodium hydroxidesolution (8 mL) and, subsequently, ethanol (3 mL) were added, and themixture was stirred at 60° C. for 2 hours. To the reaction solution wereadded 2N aqueous hydrochloric acid solution and ethyl acetate, the ethylacetate layer was separated, and the aqueous layer was extracted withethyl acetate. The solvent was distilled off, and the resulting residuewas purified by silica gel chromatography. Elution with ethylacetate-methanol, and concentration of an objective fraction afforded 84mg of compound 168C.

MS: m/z=536.25 [M+H]⁺.

Third Step

To a DMI (2 mL) solution of compound 168C (80 mg, 0.15 mmol) was addedlithium chloride (19 mg, 0.45 mmol), and the mixture was stirred at 90°C. for 2 hours. To the reaction mixture were added water and 2N aqueoushydrochloric acid solution, the precipitated solid was filtered, and theresulting solid was purified using an LCMS fractionating device. Theeluted solvent was distilled off, isopropyl ether was added to theresidue, and the precipitated solid was filtered. Washing with isopropylether and drying afforded 12 mg of compound 168.

MS: m/z=446.05 [M+H]⁺.

Reference Example 169

First Step

To an ethanol (5 mL) solution of compound 95A (WO 2006/116764, 500 mg,2.03 mmol) was added 2,2-dimethoxyethanamine (0.49 ml, 4.47 mmol), andthe mixture was stirred at 80° C. for 3 hours. After the reactionsolution was allowed to cool, acetic acid (0.27 ml, 4.69 mmol) was addedat room temperature, and the mixture was concentrated under reducedpressure. The resulting residue was dissolved in DMF (5 mL), DBU (0.66mL, 4.4 mmol) and, subsequently, methyl iodide (1.02 mL, 16.2 mmol) wereadded under nitrogen atmosphere, and the mixture was stirred at roomtemperature for 3 hours. To the reaction solution were added an aqueoussaturated sodium bicarbonate solution and ethyl acetate, the ethylacetate layer was separated, and the aqueous layer was extracted withethyl acetate. To the combined extracts was added sodium sulfate, themixture was filtered and concentrated, and the resulting residue waspurified by silica gel chromatography. Elution with chloroform-methanol(9:1) and concentration of an objective fraction afforded 258 mg ofcompound 169A as a brown oil.

¹H-NMR (CDCl₃) δ: 3.37 (6H, s), 3.80 (3H, s), 3.87 (2H, d, J=4.8 Hz),4.46 (1H, t, J=4.8 Hz), 5.30 (2H, s), 6.75 (1H, d, J=6.0 Hz), 7.30-7.41(6H, m).

Second Step

To compound 169A (1.00 g, 2.88 mmol) were added formic acid (31 mL) and,subsequently, water (5 mL), and the mixture was stirred at 70° C. for6.5 hours. To the reaction mixture were added water and ethyl acetate,the ethyl acetate layer was separated, and the aqueous layer wasextracted with ethyl acetate. After the combined extracts were washedwith an aqueous saturated sodium bicarbonate solution, and sodiumsulfate was added, then the mixture was filtered and concentrated, andthe resulting residue was purified by silica gel chromatography. Elutionwith ethyl acetate-methanol, and concentration of an objective fractionafforded a mixture of aldehyde hydride and methylacetal as a colorlesstransparent oil. The resulting oil was dissolved in dichloromethane (5mL), 1,3-diaminopropane dihydrochloride (354 mg, 2.41 mmol) and,subsequently, acetic acid (0.069 ml, 1.2 mmol) were added, and themixture was stirred at room temperature for 6 hours. The reactionsolution was diluted with dichloromethane, insolubles were filtered and,thereafter, the mixture was concentrated under reduced pressure toobtain a crude purified product of compound 169B.

MS: m/z=326.20 [M+H]⁺.

Third Step

To an acetonitrile (4 mL) solution of compound 169B (391 mg, 1.20 mmol)were added potassium carbonate (498 mg, 3.61 mmol) and, subsequently,bromomethylenedibenzene (890 mg, 3.61 mmol). After the reaction solutionwas stirred at 90° C. for 2 hours, to the reaction solution were addedwater, ethyl acetate and brine, the ethyl acetate layer was separated,and the aqueous layer was extracted with ethyl acetate once. After thecombined extracts were dried with magnesium sulfate, then the mixturewas filtered and concentrated. The resulting residue was purified bysilica gel column chromatography. Elution with ethyl acetate-methanol,and concentration of an objective fraction afforded 106 mg of compound169C as an orange solid.

MS: m/z=492.15 [M+H]⁺.

Fourth Step

To a DMI (2 mL) solution of compound 169C (105 mg, 0.214 mmol) was addedlithium chloride (27.2 mg, 0.641 mmol), and the mixture was stirred at90° C. for 3 hours. Further, lithium chloride (27.2 mg, 0.641 mmol) wasadded, and the mixture was stirred at 90° C. for 1 hour. The reactionsolution was concentrated under reduced pressure, and the resultingresidue was purified using an LCMS fractionating device. The elutedsolvent was distilled off, to the residue was added diethyl ether, andthe precipitated solid was filtered. Washing with diethyl ether, anddrying afforded 27 mg of compound 169.

¹H-NMR (CD₃OD) δ: 1.63 (1H, dd, J=13.4, 2.8 Hz), 1.84 (1H, brs),2.55-2.64 (1H, m), 2.90-3.10 (2H, m), 4.30 (1H, dd, J=14.5, 4.0 Hz),4.52 (4H, dd, J=14.5, 3.8 Hz), 4.63-4.75 (4H, m), 5.16 (1H, s), 6.16(1H, d, J=7.2 Hz), 6.78 (1H, d, J=7.2 Hz), 7.16-7.32 (10H, m).

MS: m/z=402.10 [M+H]⁺.

Reference Example 170

First Step

Compound 49F (87 mg, 0.19 mmol) was dissolved in ethanol (1 ml) and THF(1 ml), a 2N aqueous sodium hydroxide solution (0.47 ml, 0.95 mmol) wasadded, and the mixture was stirred at room temperature for 1.5 hours. Tothe reaction solution was added 2N hydrochloric acid, the mixture wasextracted with ethyl acetate, and the extract was dried with sodiumsulfate. The resulting crude product was purified by silica gel columnchromatography (chloroform-methanol 95:5→90:10, v/v) to obtain 60 mg ofcompound 170A.

¹H-NMR (CDCl₃) δ: 2.48 (1H, dd, J=13.8, 11.8 Hz), 3.27 (1H, dd, J=14.2,3.4 Hz), 3.73-3.80 (1H, m), 3.92 (1H, m), 4.16 (1H, m), 4.45 (2H, m),5.34 (1H, d, J=3.5 Hz), 5.47 (1H, d, J=10.4 Hz), 5.52 (1H, d, J=10.7Hz), 6.73 (2H, d, J=6.9 Hz), 7.18-7.42 (7H, m), 7.60 (2H, d, J=6.9 Hz),14.63 (1H, s).

Second Step

To compound 170A (57 mg, 0.13 mmol) was added trifluoroacetic acid (1ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 3 with sodiumbicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure, chloroform-ethyl etherwere added, and the precipitated solid was filtered to obtain 19 mg ofcompound 170 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 2.74 (1H, t, J=12.1 Hz), 3.10-3.22 (1H, m), 3.76(2H, m), 4.12 (1H, q, J=8.0 Hz), 4.44 (1H, m), 5.35 (1H, m), 5.49 (1H,d, J=3.4 Hz), 7.05 (5H, m), 7.77 (1H, s), 12.05 (1H, brs).

Reference Example 171

First Step

Compound 49B (950 mg, 3.35 mmol), 3-aminopropan-1-ol (277 mg, 3.69 mmol)and sodium sulfate (1.91 g, 13.4 mmol) were added to toluene (25 ml),and the mixture was stirred at room temperature for 1 hour. Boc2O (0.856ml, 3.69 mmol) was added at room temperature, and the mixture wasstirred for 18 hours. Further, Boc2O (0.400 ml, 1.72 mmol) was added atroom temperature, and the mixture was stirred for 60 hours. The reactionsolution was filtered, and the filtrate was concentrated under reducedpressure. The resulting crude product was purified by silica gel columnchromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 1.02 g ofcompound 171A as a colorless gummy substance.

Second Step

Compound 171A (1.01 g, 2.29 mmol) and palladium-active carbon (10%, wet,200 mg) were added to ethanol (20 ml), and the mixture was stirred atroom temperature for 1.5 hours under hydrogen atmosphere. Afterfiltration with celite, the solvent was concentrated under reducedpressure to obtain 755 mg of a colorless oily substance 171B.

¹H-NMR (CDCl₃) δ: 1.42 (5H, s), 1.49 (4H, s), 1.56-1.92 (2H, m), 2.49(0.4H, dd, J=13.6, 9.8 Hz), 2.62 (0.6H, dd, J=13.6, 8.5 Hz), 2.81 (0.4H,dd, J=13.5, 3.6 Hz), 3.16 (1.6H, m), 3.60-4.14 (4H, m), 5.13 (0.6H, d,J=8.8 Hz), 5.19 (0.4H, d, J=8.5 Hz), 7.22-7.37 (5H, m).

Third Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (660 mg, 1.99mmol) and compound 171B (609 mg, 1.99 mmol) were added to toluene (8ml), and the mixture was stirred at 100° C. for 1.5 hours. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 99:1, v/v) to obtain 1.02 g of compound 171C as apale yellow gummy substance.

Fourth Step

To compound 171C (991 mg, 1.60 mmol) was added 4N HCl (ethyl acetatesolution, 12 ml). After the mixture was stirred at room temperature for1 hour, the solvent was distilled off under reduced pressure.Subsequently, toluene (12 ml) and 3-aminopropan-1-ol (0.244 ml, 3.19mmol) were added, the mixture was stirred at 80° C. for 10 minutes.After the solvent was distilled off under reduced pressure, theresulting crude product was purified by silica gel column chromatography(chloroform-methanol, 99:1→95:5→90:10, v/v) to obtain 341 mg of compound171D as a yellow gummy substance and 338 mg of compound 171E as acolorless solid.

171D: ¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.1 Hz), 1.51 (1H, d, J=13.7 Hz),1.97 (1H, m), 2.91 (1H, dd, J=13.8, 9.8 Hz), 2.99-3.10 (2H, m), 3.90(1H, td, J=12.1, 2.5 Hz), 4.12 (2H, m), 4.25 (2H, m), 4.83 (2H, m), 5.33(1H, d, J=10.1 Hz), 5.51 (1H, d, J=10.1 Hz), 6.88 (2H, m), 7.23-7.40(7H, m), 7.68 (2H, m)

171E: ¹H-NMR (CDCl₃) δ: 1.19 (3H, t, J=7.2 Hz), 1.82-1.99 (2H, m), 2.73(1H, dd, J=14.0, 11.3 Hz), 3.13 (1H, m), 3.35 (1H, dd, J=14.0, 3.4 Hz),3.63 (1H, m), 3.90-4.26 (4H, m), 4.43 (1H, d, J=13.6 Hz), 5.27 (1H, t,J=3.5 Hz), 5.31 (2H, s), 6.78 (2H, dd, J=6.3, 3.2 Hz), 7.01 (1H, d,J=7.0 Hz), 7.18 (3H, t, J=3.1 Hz), 7.28-7.39 (3H, m), 7.67 (2H, m).

Fifth Step

Compound 171D (329 mg, 0.673 mmol) was dissolved in ethanol (2 ml) andTHF (4 ml), a 2N aqueous sodium hydroxide solution (1.69 ml, 3.38 mmol)was added, and the mixture was stirred at room temperature for 1 hour.To the reaction solution was added 2N hydrochloric acid, the mixture wasextracted with ethyl acetate, and the extract was dried with sodiumsulfate. The solvent was concentrated under reduced pressure to obtain215 mg of compound 171F as a colorless solid.

MS: m/z=461 [M+H]⁺.

Sixth Step

To compound 171F (50 mg, 0.11 mmol) was added trifluoroacetic acid (2ml), and the mixture was stirred at room temperature for 1 hour. Afterconcentration under reduced pressure, pH was adjusted to 6 with sodiumbicarbonate water and 2N hydrochloric acid, the mixture was extractedwith chloroform, and the extract was dried with sodium sulfate. Afterthe solvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 24 mg of compound 171 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.63 (1H, d, J=12.6 Hz), 1.83 (1H, m), 2.96-3.29(3H, m), 4.05 (2H, m), 4.55 (1H, dd, J=13.2, 4.4 Hz), 5.08 (1H, dd,J=9.2, 5.4 Hz), 5.30 (1H, s), 7.19 (5H, m), 8.09 (1H, s), 12.84 (1H,brs).

MS: m/z=371 [M+H]⁺.

Reference Example 172

According to Reference example 171, using compound 171E, compound 172was synthesized by the same procedure.

¹H-NMR (DMSO-d₆) δ: 1.91 (2H, m), 2.94 (1H, dd, J=14.0, 10.8 Hz),3.11-3.21 (3H, m), 3.71 (1H, m), 4.19 (1H, m), 4.29-4.35 (1H, m),5.08-5.14 (1H, m), 5.47 (1H, d, J=4.0 Hz), 6.92-7.22 (5H, m), 7.71 (1H,s), 12.80 (1H, brs), 15.06 (1H, brs).

MS: m/z=371 [M+H]⁺.

Reference Example 173

First Step

Compound 171F (159 mg, 0.345 mmol) was added to diphenyl ether (2.5 ml),and the mixture was stirred at 245° C. for 1 hour under microwaveirradiation. The reaction solution was poured into n-hexane, and theprecipitated solid was filtered. The resulting crude product waspurified by silica gel column chromatography (chloroform-methanol,95:5→90:10, v/v) to obtain compound 173A.

Second Step

To compound 173A obtained in the first step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 10 mg of compound 173 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.55-1.86 (2H, m), 2.84-3.26 (3H, m), 3.92-4.09 (2H,m), 4.55 (2H, m), 5.15 (1H, s), 5.89 (1H, d, J=7.5 Hz), 7.17 (6H, m),12.11 (1H, brs)

MS: m/z=327 [M+H]⁺.

Reference Example 174

According to Reference example 173, compound 174 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.86 (2H, m), 2.87 (1H, t, J=12.3 Hz), 3.18 (2H, m),3.68 (1H, t, J=10.4 Hz), 4.16 (1H, d, J=10.1 Hz), 4.29 (1H, d, J=12.4Hz), 4.71 (1H, d, J=9.2 Hz), 5.37 (1H, d, J=3.5 Hz), 5.75 (1H, d, J=7.5Hz), 7.00 (6H, m), 12.51 (1H, brs).

MS: m/z=327 [M+H]⁺.

Reference Example 175

First Step

To Dess-Martin Periodinane (0.3M, methylene chloride solution, 25.0 ml,7.50 mmol) was added dropwise a methylene chloride solution (10 ml) ofcompound 2B (1.98 g, 5.48 mmol) at 0° C. After stirring at roomtemperature for 3 hours, the reaction mixture was poured into a 1Naqueous sodium hydroxide solution, and the mixture was extracted withethyl ether. The organic layer was washed with a 1N aqueous sodiumhydroxide solution and an aqueous saturated sodium chloride solution,and dried with magnesium sulfate. After the solvent was distilled offunder reduced pressure, purification was performed by silica gel columnchromatography (n-hexane-ethyl acetate, 2:1, v/v) to obtain 1.73 g ofcompound 175A as a white solid.

¹H-NMR (CDCl₃) δ: 4.55 (1H, d, J=7.3 Hz), 5.09 (2H, s), 5.14 (2H, m),7.22-7.35 (15H, m), 9.62 (1H, s).

Second Step

Compound 175A (1.30 g, 4.59 mmol), 3-aminopropan-1-ol (379 mg, 5.05mmol) and sodium sulfate (3.26 g, 22.4 mmol) were added to toluene (40ml), and the mixture was stirred at room temperature for 1 hour. Boc2O(1.17 ml, 5.05 mmol) was added at room temperature, and the mixture wasstirred for 18 hours. Boc2O (1.17 ml, 5.05 mmol) and sodium sulfate(3.26 g, 22.4 mmol) were added, and the mixture was stirred for 60hours. The reaction solution was filtered, and the filtrate wasconcentrated under reduced pressure. The resulting crude product waspurified by silica gel column chromatography (n-hexane-ethyl acetate,1:1, v/v) to obtain 635 mg of compound 175B as a colorless solid.

Third Step

Compound 175B (632 mg, 1.22 mmol) and palladium-active carbon (10%, wet,100 mg) were added to ethanol (10 ml) and THF (5 ml), and the mixturewas stirred at room temperature for 3 hours under hydrogen atmosphere.After filtration with celite, the solvent was concentrated under reducedpressure to obtain 502 mg of a colorless oily substance 175C.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.77 (2H, m), 3.18-3.27 (1H, m),3.43-3.51 (1H, m), 4.04 (4H, m), 4.92 (1H, d, J=4.7 Hz), 7.28 (10H, m).

Fourth Step

Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (390 mg, 1.22mmol) and compound 175C (468 mg, 1.22 mmol) were added to toluene (5ml), and the mixture was stirred at 100° C. for 2 hours. After thesolvent was distilled off under reduced pressure, the resulting crudeproduct was purified by silica gel column chromatography (n-hexane-ethylacetate, 1:1, v/v) to obtain 391 mg of compound 175D as a pale yellowgummy substance.

Fifth Step

To compound 175D (388 mg, 0.568 mmol) was added 4N HCl (ethyl acetatesolution, 4 ml). After the mixture was stirred at room temperature for 1hour, the solvent was distilled off under reduced pressure.Subsequently, toluene (4 ml) and 3-aminopropan-1-ol (0.0870 ml, 1.14mmol) were added, and the mixture was stirred at 80° C. for 5 hours.After the solvent was distilled off under reduced pressure, theresulting crude product was purified by silica gel column chromatography(chloroform-methanol, 98:2, v/v) to obtain 57 mg of compound 175E as ayellow gummy substance and 44 mg of compound 175F as a brown gummysubstance.

175E: ¹H-NMR (CDCl₃) δ: 1.91-2.00 (2H, m), 2.87 (1H, m), 3.78 (3H, s),3.87-4.15 (3H, m), 4.61 (1H, d, J=12.1 Hz), 4.78 (2H, m), 5.33 (1H, d,J=10.2 Hz), 5.63 (1H, d, J=10.2 Hz), 6.95 (2H, m), 7.13-7.53 (12H, m),7.76 (2H, m)

17F: ¹H-NMR (CDCl₃) δ: 1.83-1.97 (2H, m), 3.12-3.22 (1H, m), 3.50 (1H,m), 3.85 (3H, s), 3.90 (1H, m), 4.34-4.40 (1H, m), 4.74 (1H, d, J=8.6Hz), 4.84-4.89 (1H, m), 5.09 (1H, d, J=3.3 Hz), 5.15 (1H, d, J=9.9 Hz),5.26 (1H, d, J=9.6 Hz), 7.08-7.50 (13H, m), 7.65-7.77 (3H, m).

Sixth Step

Compound 175E (57 mg, 0.10 mmol) was dissolved in THF (0.5 ml) andethanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.25 ml, 0.50mmol) was added at room temperature, and the mixture was stirred for 1hour. After 1N hydrochloric acid was added, and the mixture wasextracted with chloroform, the extract was dried with sodium sulfate.The solvent was distilled off under reduced pressure, the resultingcrude product was purified by silica gel column chromatography(chloroform-methanol, 98:2, v/v) to obtain compound 175G.

Seventh Step

To compound 175G obtained in the sixth step was added trifluoroaceticacid (1 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 3 withsodium bicarbonate water and 2N hydrochloric acid, and the mixture wasextracted with chloroform, and dried with sodium sulfate. After thesolvent was distilled off under reduced pressure,chloroform-methanol-ethyl ether were added, and the precipitated solidwas filtered to obtain 11 mg of compound 175 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.50 (1H, d, J=13.1 Hz), 1.79 (1H, m), 3.17 (1H, m),3.86 (1H, t, J=11.0 Hz), 4.03 (1H, dd, J=10.8, 4.1 Hz), 4.46 (1H, d,J=12.0 Hz), 4.53 (1H, dd, J=12.7, 4.2 Hz), 4.84 (1H, s), 5.85 (1H, d,J=11.7 Hz), 7.22 (7H, m), 7.44 (2H, t, J=7.6 Hz), 7.65 (2H, d, J=7.3Hz), 8.14 (1H, s), 12.75 (1H, s), 15.33 (1H, brs).

MS: m/z=447 [M+H]⁺.

Reference Example 176

According to Reference example 175, using compound 175F, compound 176was synthesized by the same procedure.

¹H-NMR (DMSO-d₆) δ: 1.75 (2H, m), 3.17 (2H, m), 3.43 (1H, m), 3.60 (1H,d, J=10.7 Hz), 4.31 (1H, d, J=12.7 Hz), 4.73 (1H, d, J=9.8 Hz), 5.52(1H, d, J=3.4 Hz), 5.87 (1H, dd, J=9.9, 3.4 Hz), 7.10 (7H, m), 7.29 (2H,t, J=7.5 Hz), 7.58 (2H, d, J=7.3 Hz), 8.37 (1H, s), 12.65 (1H, brs).

MS: m/z=447 [M+H]⁺.

Reference Example 177

First Step

Tert-butyl pyrazolidine-1-carboxylate (275 mg, 1.60 mmol) synthesizedaccording to the method of the reference (Journal of the ChemicalSociety, Perkin Transactions 1: Organic and Bio-Organic Chemistry(1972-1999), 1975, p. 1712), and compound 95B (409 mg, 1.45 mmol) weredissolved in pyridine (5 ml), HATU (607 mg, 1.60 mmol) was added at roomtemperature, and the mixture was stirred for 18 hours. The reactionsolution was poured into 1N hydrochloric acid, and the mixture wasextracted with ethyl acetate, and dried with sodium sulfate. The solventwas distilled off under reduced pressure, and the resulting crudeproduct was purified by silica gel column chromatography(chloroform-methanol, 97 3→95:5, v/v) to obtain 529 mg of compound 177Aas a yellow solid.

¹H-NMR (CDCl₃) δ: 1.35 (9H, s), 1.88-2.10 (2H, m), 3.04 (1H, s), 3.31(1H, s), 3.86 (2H, m), 4.96 (1H, d, J=9.3 Hz), 5.45 (1H, d, J=11.0 Hz),6.56 (1H, d, J=6.7 Hz), 7.29-7.43 (6H, m).

Second Step

To compound 177A (525 mg, 1.31 mmol) was added 4N HCl (dioxane solution,6 ml). After the mixture was stirred at room temperature for 1.5 hours,the solvent was distilled off under reduced pressure to obtain 413 mg ofcompound 177B as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.95-2.05 (2H, m), 2.78 (2H, t, J=6.6 Hz), 3.41-3.54(2H, m), 5.11 (2H, s), 7.38 (5H, m), 7.46 (1H, d, J=6.6 Hz), 8.36 (1H,d, J=6.7 Hz).

Third Step

Compound 177B (100 mg, 0.298 mmol) was added to ethanol (2 ml),2,2-diphenylacetaldehyde (58 mg, 0.30 mmol), triethylamine (0.083 ml,0.596 mmol) and acetic acid (0.051 ml, 0.89 mmol) were added, and themixture was stirred at 80° C. for 3 hours. The reaction solution waspoured into water, the mixture was extracted with chloroform, and theextract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting crude product was purified bysilica gel column chromatography (chloroform-methanol,97:3→95:5→93:7→90:10, v/v) to obtain 106 mg of compound 177C as a yellowgummy substance.

MS: m/z=478 [M+H]⁺.

Fourth Step

To compound 177C obtained in the third step was added trifluoroaceticacid (2 ml), and the mixture was stirred at room temperature for 1 hour.After concentration under reduced pressure, pH was adjusted to 6 withsodium bicarbonate water and 2N hydrochloric acid, the mixture wasextracted with chloroform, and the extract was dried with sodiumsulfate. After the solvent was distilled off under reduced pressure,methylene chloride-ethyl ether were added, and the precipitated solidwas filtered to obtain 7 mg of compound 177 as a colorless solid.

¹H-NMR (DMSO-d₆) δ: 1.95 (2H, m), 2.76 (1H, m), 2.96-3.17 (2H, m), 4.04(1H, m), 4.68 (1H, d, J=10.4 Hz), 5.66 (1H, d, J=7.3 Hz), 6.56 (1H, d,J=10.5 Hz), 7.03 (1H, d, J=7.2 Hz), 7.17 (6H, m), 7.34 (2H, t, J=7.3Hz), 7.55 (2H, d, J=7.5 Hz).

MS: m/z=388 [M+H]⁺.

Reference Example 178

According to Reference example 177, compound 178 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.55 (4H, m), 2.35-7.49 (1H, m), 2.39 (1H, t, J=12.6Hz), 2.77 (1H, t, J=10.0 Hz), 3.09 (1H, d, J=11.4 Hz), 4.34 (1H, d,J=12.8 Hz), 4.55 (1H, d, J=10.8 Hz), 5.71 (1H, d, J=7.0 Hz), 6.17 (1H,d, J=10.8 Hz), 6.82 (1H, d, J=7.3 Hz), 7.13-7.40 (8H, m), 7.48 (2H, d,J=7.3 Hz).

MS: m/z=402 [M+H]⁺.

Reference Example 179

According to Reference example 177, compound 179 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, m), 2.68 (2H, m), 3.21 (1H, m), 4.04 (1H,m), 4.40 (1H, d, J=10.8 Hz), 5.77 (1H, t, J=5.2 Hz), 6.26 (1H, d, J=10.8Hz), 6.78 (1H, d, J=7.3 Hz), 7.27 (8H, m), 7.53 (2H, d, J=7.2 Hz).

MS: m/z=416 [M+H]⁺.

Reference Example 180

According to Reference example 177, compound 180 was synthesized by thesame procedure.

¹H-NMR (DMSO-d₆) δ: 2.78-3.74 (7H, m), 4.17 (1H, m), 4.49 (1H, d, J=10.8Hz), 5.79 (1H, d, J=7.2 Hz), 6.32 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=7.2Hz), 7.28 (8H, m), 7.55 (2H, d, J=7.6 Hz).

MS: m/z=418 [M+H]⁺.

Using amines which are commercially available or known in the referencesand halides which are commercially available or known in the references,and according to the method of Reference example 12, Reference examples181 to 187 were synthesized.

Reference Example 181

MS: m/z=433 [M+H]⁺.

Reference Example 182

MS: m/z=459 [M+H]⁺.

Reference Example 183

MS: m/z=529 [M+H]⁺.

Reference Example 184

MS: m/z=477 [M+H]⁺.

Reference Example 185

MS: m/z=473 [M+H]⁺.

Reference Example 186

Reference Example 187

MS: m/z=461 [M+H]⁺

Reference Example 188

According to Reference example 12 and Reference example 129, Compound188 was synthesized by the same procedure.

MS: m/z=449 [M+H]⁺.

Using amines which are commercially available or known in the referencesand halides which are commercially available or known in the references,and according to Reference example 95, Compounds 189-229 weresynthesized by the same procedure.

Reference Example 189

MS: m/z=399 [M+H]⁺

Reference Example 190

Reference Example 191

MS: m/z=470 [M+H]⁺

Reference Example 192

MS: m/z=422 [M+H]⁺.

Reference Example 193

MS: m/z=422 [M+H]⁺

Reference Example 194

MS: m/z=486 [M+H]⁺

Reference Example 195

MS: m/z=365 [M+H]⁺

Reference Example 196

MS: m/z=418 [M+H]⁺

Reference Example 197

MS: m/z=339 [M+H]⁺

Reference Example 198

MS: m/z=344 [M+H]⁺

Reference Example 199

MS: m/z=383 [M+H]⁺

Reference Example 200

MS: m/z=339 [M+H]⁺

Reference Example 201

MS: m/z=440 [M+H]⁺

Reference Example 202

MS: m/z=365 [M+H]⁺

Reference Example 203

MS: m/z=396 [M+H]⁺

Reference Example 204

MS: m/z=370 [M+H]⁺

Reference Example 205

MS: m/z=390 [M+H]⁺

Reference Example 206

MS: m/z=420 [M+H]⁺

Reference Example 207

MS: m/z=350 [M+H]⁺

Reference Example 208

MS: m/z=428 [M+H]⁺

Reference Example 209

MS: m/z=386 [M+H]⁺

Reference Example 210

MS: m/z=378 [M+H]⁺

Reference Example 211

MS: m/z=366 [M+H]⁺

Reference Example 212

MS: m/z=362 [M+H]⁺

Reference Example 213

MS: m/z=358 [M+H]⁺

Reference Example 214

MS: m/z=350 [M+H]⁺

Reference Example 215

MS: m/z=350 [M+H]⁺

Reference Example 216

MS: m/z=411 [M+H]⁺

Reference Example 217

MS: m/z=445 [M+H]⁺

Reference Example 218

MS: m/z=366 [M+H]⁺

Reference Example 219

MS: m/z=354 [M+H]⁺

Reference Example 220

MS: m/z=368 [M+H]⁺

Reference Example 221

MS: m/z=314 [M+H]⁺

Reference Example 222

MS: m/z=330 [M+H]⁺

Reference Example 223

MS: m/z=346 [M+H]⁺

Reference Example 224

MS: m/z=418 [M+H]⁺.

Reference Example 225

MS: m/z=445 [M+H]⁺.

Reference Example 226

MS: m/z=473 [M+H]⁺.

Reference Example 227

MS: m/z=444 [M+H]⁺.

Reference Example 228

MS: m/z=434 [M+H]⁺

Reference Example 229

MS: m/z=443 [M+H]⁺.

Reference Example 230

According to Reference example 128, compound 230 was synthesized by thesame procedure.

MS: m/z=461 [M+H]⁺.

Reference Example 231

According to Reference example 129, compound 231 was synthesized by thesame procedure.

MS: m/z=420 [M+H]⁺.

Reference Example 232

According to Reference example 129, compound 232 was synthesized by the

MS: m/z=434 [M+H]⁺.

Reference Example 233

According to Reference example 130, compound 233 was synthesized by thesame procedure.

MS: m/z=433 [M+H]⁺.

Reference Example 234

According to Reference example 130, compound 234 was synthesized by thesame procedure.

MS: m/z=447 [M+H]⁺.

Reference Example 235

According to Reference example 130, compound 235 was synthesized by thesame procedure.

MS: m/z=473 [M+H]⁺.

Reference Example 236

According to Reference example 130, compound 236 was synthesized by thesame procedure.

MS: m/z=447 [M+H]⁺.

Reference Example 237

According to Reference example 130, compound 237 was synthesized by thesame procedure.

MS: m/z=487 [M+H]⁺.

Reference Example 238

According to Reference example 130, compound 238 was synthesized by thesame procedure.

MS: m/z=509 [M+H]⁺.

Reference Example 239

MS: m/z=376 [M+H]⁺

According to Reference example 157, compound 239 was synthesized by thesame procedure.

Using amines which are commercially available or known in the referencesand alcohols which are commercially available or known in thereferences, and according to the method of Reference example 107,Examples 240 to 245 were synthesized.

Reference Example 240

¹H-NMR (CDCl₃) δ: 1.05 (3H, d, J=6.9 Hz), 1.04-1.14 (4H, m), 4.49 (1H,d, J=13.2 Hz), 4.83 (1H, d, J=13.2 Hz), 4.91-4.99 (1H, m), 5.73 (1H, d,J=7.8 Hz), 6.50 (1H, s), 6.70 (1H, d, J=7.8 Hz), 7.12-7.30 (4H, m),7.33-7.43 (2H, m), 7.46-7.54 (1H, m), 8.06 (1H, d, J=7.5 Hz).

Reference Example 241

MS: m/z=478 [M+H]⁺

Reference Example 242

MS: m/z=478 [M+H]⁺

Reference Example 243

MS: m/z=478 [M+H]⁺

Reference Example 244

¹H-NMR (CDCl₃) δ: 1.14 (6H, d, J=6.9 Hz), 4.59 (1H, d, J=12.6 Hz), 4.77(1H, d, J=12.6 Hz), 4.81-4.91 (1H, m), 5.82 (1H, d, J=7.5 Hz), 5.82 (1H,s), 6.71 (1H, brs), 6.78 (1H, brs), 6.87 (1H, d, J=7.5 Hz), 7.05 (1H,brs), 7.16 (1H, brs), 7.25 (1H, brs), 7.41 (1H, brs).

Reference Example 245

MS: m/z=490 [M+H]⁺.

Reference Example 246

First Step

To a dimethylformamide (20 ml) solution of compound 246A (5.30 g, 18.76mmol) and potassium carbonate (5.19 g, 27.53 mmol) was added benzylbromide (3.21 g, 18.76 mmol), and the mixture was stirred at roomtemperature for 1 hour. To the reaction solution was added ethyl acetate(80 ml), insolubles were filtered off, and 1N hydrochloric acid wasadded. The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate two times. The combined organic layers werewashed with water once and, further, washed with sodium bicarbonatewater once, and with an aqueous saturated sodium chloride solution once.The resulting solution was dried with sodium sulfate, and the solventwas distilled off to obtain 6.98 g of compound 246B as an oil.

¹H-NMR (CDCl₃) δ: 5.36 (2H, s), 7.35-7.47 (6H, m), 7.78 (1H, d, J=8.4Hz), 8.01 (11H, d, J=2.1 Hz).

Second Step

To a dimethylformamide (15 ml) solution of compound 246B (3 g, 8.05mmol) and 1-chloro-3-ethynylbenzene (1.32 g, 9.66 mmol) andtriethylamine (4.07 g, 40.25 mmol) were added copper chloride (76.6 mg,0.403 mmol) and dichlorobis(triphenylphosphine)palladium (282.5 mg,0.403 mmol) under nitrogen atmosphere, and the mixture was stirred atroom temperature for 5 hours. The reaction solution was diluted withwater, and the mixture was extracted with ethyl acetate three times. Thecombined extracts were washed with water three times, and dried withsodium sulfate, then the solvent was distilled off. The resulting oilwas purified by silica gel column chromatography. The materials wereeluted firstly with hexane and, then, with hexane-ethyl acetate (7:3,v/v). Concentration of an objective fraction afforded 3.10 g of compound246C as an oil.

¹H-NMR (CDCl₃) δ: 5.39 (2H, s), 7.21-7.46 (9H, m), 7.62 (1H, d, J=2.1Hz), 7.98 (1H, d, J=8.4 Hz).

Third Step

To a methanol (30 ml) solution of compound 246C (3.10 g, 8.05 mmol) wasadded 10% palladium carbon (620 mg, 20 wt %), and the mixture wasstirred at room temperature under 1 atm hydrogen atmosphere. Thereaction solution was filtered with celite, the solvent was distilledoff, to the resulting crude product were added ethyl acetate-diisopropylether, and the precipitated residue was filtered to obtain 618 mg ofcompound 246D as a solid.

¹H-NMR (CDCl₃) δ: 2.90 (2H, dd, J=7.8 Hz, 10.8 Hz), 3.29 (2H, dd, J=7.5Hz, 10.5 Hz), 7.06-7.09 (1H, m), 7.18-7.25 (4H, m), 7.31 (1H, dd, J=2.1Hz, 8.7 Hz), 8.05 (1H, d, J=8.4 Hz).

Fourth Step

To compound 246D (2.20 g, 7.45 mmol) was added polyphosphoric acid (20g), and the mixture was stirred at 200° C. for 1 hour. After cooled toroom temperature, water was added, and the mixture was extracted withethyl acetate three times. The combined extracts were washed withsaturated sodium bicarbonate water once, and dried with sodium sulfateand, thereafter, the solvent was distilled off. The resulting oil waspurified by silica gel column chromatography. The materials were elutedfirstly with hexane and, then, with hexane-ethyl acetate (7:3, v/v).Concentration of an objective fraction afforded 1.05 g of compound 246Eas an oil.

¹H-NMR (CDCl₃) δ: 3.17 (4H, s), 7.24 (2H, d, J=2.1 Hz), 7.32 (2H, dd,J=2.1 Hz, 8.4 Hz, 8.00 (2H, d, J=8.4 Hz).

Fifth Step

A methanol (10 ml) suspension of sodium borohydride (409 mg, 10.82 mmol)was cooled to 1 to 3° C., and compound 246E (1.0 g, 3.61 mmol) was addedwhile the same temperature was retained. After the reaction solution wasstirred at the same temperature for 30 minutes, water was added. Theprecipitated solid was filtered to obtain 968 mg of compound 246F.

¹H-NMR (CDCl₃) δ: 2.25 (1H, d, J=3.0 Hz), 3.05-3.16 (2H, m), 3.27-3.38(2H, m), 5.95 (1H, d, J=3.0 Hz), 7.14-7.17 (4H, m), 7.39 (2H, d, J=8.1Hz).

Sixth Step

According to Reference example 107, compound 246 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.79(1H, ddd, J=4.5 Hz, 4.5 Hz, 14.4 Hz), 2.99-3.11 (1H, m), 3.50 (1H, ddd,J=4.8 Hz, 4.8 Hz), 17.7 Hz), 4.21-4.33 (1H, m), 4.23 (1H, d, J=12.9 Hz),4.62-4.74 (2H, m), 5.04 (1H, s), 5.84 (1H, d, J=7.8 Hz), 6.57 (1H, d,J=8.1 Hz), 6.65-6.72 (2H, m), 6.89-6.92 (1H, m), 7.11-7.30 (4H, m).

Using amines which are commercially available or known in the referencesand intermediates corresponding to compound 246A to compound 246F whichare commercially available or known in the references, and according tothe method of Reference example 246, compounds 247 to 284 weresynthesized.

Reference Example 247

MS: m/z=457 [M+H]⁺.

Reference Example 248

MS: m/z=485 [M+H]⁺.

Reference Example 249

MS: m/z=471 [M+H]⁺.

Reference Example 250

MS: m/z=457 [M+H]⁺.

Reference Example 251

Reference Example 252

MS: m/z=485 [M+H]⁺.

Reference Example 253

MS: m/z=471 [M+H]⁺.

Reference Example 254

MS: m/z=487 [M+H]⁺.

Reference Example 255

MS: m/z=469 [M+H]⁺.

Reference Example 256

MS: m/z=470 [M+H]⁺.

Reference Example 257

MS: m/z=434 [M+H]⁺.

Reference Example 258

¹H-NMR (DMSO-d₆) δ: 2.88 (3H, m), 3.43 (2H, m), 3.69 (1H, dt, J=16.9,5.1 Hz), 4.01 (1H, d, J=13.4 Hz), 4.07-4.17 (2H, m), 4.97 (1H, d, J=13.4Hz), 5.24 (1H, s), 5.50 (1H, d, J=7.6 Hz), 6.73 (1H, d, J=7.2 Hz),6.85-6.94 (2H, m), 7.14-7.41 (6H, m), 11.73 (1H, s).

MS: m/z=432 [M+H]⁺.

Reference Example 259

¹H-NMR (DMSO-d₆) δ: 2.80 (1H, td, J=9.6, 4.5 Hz), 2.86-2.99 (1H, m),3.00-3.18 (1H, m), 3.67 (1H, dt, J=17.1, 5.0 Hz), 4.03-4.19 (2H, m),4.32-4.52 (1H, m), 5.05 (1H, d, J=13.3 Hz), 5.26 (1H, s), 5.53 (1H, d,J=7.6 Hz), 6.17 (1H, tt, J=55.0, 3.5 Hz), 6.72 (1H, d, J=7.5 Hz),6.87-6.94 (2H, m), 7.12-7.27 (3H, m), 7.30-7.43 (3H, m).

MS: m/z=438 [M+H]⁺.

Reference Example 260

MS: m/z=460 [M+H]⁺.

Reference Example 261

MS: m/z=474 [M+H]⁺.

Reference Example 262

¹H-NMR (DMSO-d₆) δ: 2.80 (1H, dt, J=14.2, 5.1 Hz), 2.86-2.99 (1H, m),3.00-3.18 (1H, m), 3.68 (1H, dt, J=16.9, 5.3 Hz), 4.05 (1H, d, J=13.3Hz), 4.07-4.32 (2H, m), 4.37-4.52 (1H, m), 4.53-4.67 (1H, m), 5.02 (1H,d, J=13.0 Hz), 5.26 (1H, s), 5.50 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.6Hz), 6.85-6.94 (2H, m), 7.12-7.27 (3H, m), 7.30-7.43 (3H, m).

MS: m/z=420 [M+H]⁺.

Reference Example 263

¹H-NMR (DMSO-d₆) δ: 2.76-3.00 (2H, m), 3.46-3.73 (2H, m), 4.06-4.22 (2H,m), 4.77-4.91 (1H, m), 5.15 (1H, d, J=12.9 Hz), 5.24 (1H, s), 5.56 (1H,d, J=7.7 Hz), 6.72 (1H, d, J=7.1 Hz), 6.88-6.95 (1H, m), 6.96 (1H, d,J=7.7 Hz), 7.09-7.41 (7H, m).

MS: m/z=456 [M+H]⁺

Reference Example 264

¹H-NMR (DMSO-d₆) δ: 2.74-2.99 (2H, m), 3.62-3.73 (1H, m), 4.01-4.20 (3H,m), 5.12 (1H, d, J=13.2 Hz), 5.15 (1H, d, J=15.7 Hz), 5.34 (1H, s), 5.52(1H, d, J=7.7 Hz), 6.78 (1H, d, J=8.0 Hz), 6.89-6.96 (2H, m), 7.10-7.23(5H, m), 7.27-7.35 (3H, m), 7.43 (1H, d, J=7.7 Hz), 7.79 (1H, td, J=7.6,1.8 Hz), 8.45-8.50 (1H, m).

MS: m/z=465 [M+H]⁺.

Reference Example 265

¹H-NMR (DMSO-d₆) δ: 1.32 (9H, s), 2.76-2.86 (1H, m), 2.87-3.01 (1H, m),3.59-3.70 (1H, m), 4.12-4.25 (1H, m), 4.29 (1H, d, J=13.5 Hz), 4.90 (1H,d, J=13.2 Hz), 5.20 (1H, s), 5.49 (1H, d, J=7.4 Hz), 6.75 (1H, d, J=8.0Hz), 6.81 (1H, d, J=7.4 Hz), 6.91 (1H, t, J=6.6 Hz), 7.12-7.21 (2H, m),7.22-7.30 (1H, m), 7.33-7.38 (2H, m), 7.46 (1H, d, J=7.4 Hz).

MS: m/z=430 [M+H]⁺.

Reference Example 266

¹H-NMR (DMSO-d₆) δ: 1.05 (3H, t, J=7.2 Hz), 2.80 (1H, dt, J=14.4, 5.1Hz), 2.85-2.99 (2H, m), 3.68 (1H, dt, J=16.8, 5.0 Hz), 3.74-3.87 (1H,m), 4.02 (1H, d, J=13.3 Hz), 4.06-4.19 (1H, m), 4.98 (1H, d, J=13.1 Hz),5.22 (1H, s), 5.48 (1H, d, J=7.6 Hz), 6.73 (1H, d, J=7.5 Hz), 6.83-6.94(2H, m), 7.12-7.40 (6H, m).

MS: m/z=402 [M+H]⁺.

Reference Example 267

¹H-NMR (CDCl₃) δ: 1.74-1.86 (2H, m), 2.71-2.82 (1H, m), 2.83-2.93 (1H,m), 2.98-3.11 (1H, m), 3.25 (3H, s), 3.39 (2H, t, J=5.4 Hz), 3.62-3.74(1H, m), 4.02-4.14 (2H, m), 4.16-4.28 (1H, m), 4.82 (1H, d, J=13.2 Hz),5.03 (1H, s), 5.76 (1H, d, J=7.7 Hz), 6.58 (1H, d, J=7.7 Hz), 6.64 (1H,d, J=7.4 Hz), 6.89-6.97 (1H, m), 7.12-7.39 (6H, m).

MS: m/z=446 [M+H]⁺.

Reference Example 268

¹H-NMR (CDCl₃) δ: 1.09 (3H, t, J=7.0 Hz), 2.65-2.77 (1H, m), 2.83-2.94(1H, m), 2.97-3.10 (1H, m), 3.40 (2H, q, J=7.0 Hz), 3.45-3.52 (1H, m),3.55-3.64 (1H, m), 3.65-3.76 (1H, m), 4.00-4.15 (2H, m), 4.36-4.45 (1H,m), 4.90 (1H, d, J=13.5 Hz), 5.02 (1H, s), 5.79 (1H, d, J=7.7 Hz), 6.59(1H, d, J=7.7 Hz), 6.63 (1H, d, J=7.4 Hz), 6.90-6.97 (1H, m), 7.13-7.39(6H, m).

MS: m/z=446 [M+H]⁺.

Reference Example 269

MS: m/z=480 [M+H]⁺.

Reference Example 270

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.85 (2H, m), 3.68 (1H, m), 4.16 (1H,m), 4.29 (1H, d, J=13.3 Hz), 4.45 (1H, d, J=17.1 Hz), 5.12 (1H, d,J=13.1 Hz), 5.26 (1H, d, J=17.4 Hz), 5.36 (1H, s), 5.55 (1H, d, J=7.6Hz), 6.74 (1H, d, J=7.6 Hz), 6.89-7.38 (8H, m).

MS: m/z=470 [M+H]⁺.

Reference Example 271

¹H-NMR (DMSO-d₆) δ: 2.87 (2H, m), 3.61-3.69 (1H, m), 4.15 (1H, m), 4.18(1H, d, J=13.2 Hz), 4.51 (1H, d, J=15.9 Hz), 5.08 (1H, d, J=13.1 Hz),5.21 (1H, s), 5.22 (1H, d, J=15.6 Hz), 5.52 (1H, d, J=7.6 Hz), 6.72 (1H,d, J=7.5 Hz), 6.89-7.32 (8H, m), 7.76 (2H, s).

MS: m/z=471 [M+H]⁺.

Reference Example 272

MS: m/z=476 [M+H]⁺

Reference Example 273

¹H-NMR (CDCl₃) δ: 2.84-2.93 (1H, m), 2.98 (3H, s), 2.98-3.09 (1H, m),3.66-3.75 (1H. m), 3.99-4.15 (1H, m), 4.06 (1H, d, J=12.9 Hz), 4.80 (1H,d, J=13.2 Hz), 5.03 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.56 (1H, d, J=7.5Hz), 6.63 (1H, d, J=6.6 Hz), 6.90-6.96 (1H, m), 7.14-7.37 (6H, m).

Reference Example 274

MS: m/z=470 [M+H]⁺.

Reference Example 275

MS: m/z=470 [M+H]⁺

Reference Example 276

MS: m/z=460 [M+H]⁺

Reference Example 277

MS: m/z=486 [M+H]⁺.

Reference Example 278

MS: m/z=446 [M+H]⁺

Reference Example 279

¹H-NMR (CDCl₃) δ: 1.08-1.21 (6H, m), 2.84 (1H, ddd, J=4.8 Hz, 4.8 Hz,14.4 Hz), 2.97-3.08 (1H, m), 3.54 (1H, ddd, J=4.8 Hz, 6.6 Hz, 17.1 Hz),4.09-4.26 (1H, m), 4.24 (1H, d, J=13.2 Hz), 4.64-4.74 (m, 1H), 4.70 (1H,d, J=13.2 Hz), 4.94 (1H, s), 5.81 (1H, d, J=7.8 Hz), 6.42 (1H, dd, J=2.7Hz, 9.0 Hz), 6.67 (1H, d, J=7.8 Hz), 6.89-7.12 (4H, m), 7.19-7.36 (1H,m).

Reference Example 280

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.84(1H, ddd, J=4.8 Hz, 5.1 Hz, 14.4 Hz), 2.96-3.07 (1H, m), 3.55 (1H, ddd,J=4.8 Hz, 5.1 Hz, 17.4 Hz), 4.11-4.23 (1H, m), 4.21 (1H, d, J=12.9 Hz),4.65-4.74 (1H, m), 4.70 (1H, d, J=12.9 Hz), 4.95 (1H, s), 5.78 (1H, d,J=7.8 Hz), 6.63 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=2.1 Hz), 7.06 (1H, d,J=8.4 Hz), 7.18 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.23-7.26 (2H, m), 7.24 (1H,dd, J=2.1 Hz, 8.1 Hz).

Reference Example 281

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, J=6.6 Hz), 1.20 (3H, d, J=6.9 Hz),2.90-3.32 (1H, m), 3.36 (1H, ddd, J=4.5 Hz, 4.5 Hz, 9.6 Hz), 3.42-3.51(1H, m), 3.95-4.02 (1H, m), 4.28 (1H, d, J=12.9 Hz), 4.64-4.75 (1H, m),1.89 (1H, d, J=12.9 Hz), 5.15 (1H, s), 5.80 (1H, d, J=7.5 Hz), 6.46-6.49(1H, m), 6.70 (1H, d, J=7.8 Hz), 6.88-7.00 (2H, m), 7.03-7.06 (1H, m),7.11-7.22 (2H, m).

Reference Example 282

¹H-NMR (CDCl₃) δ: 1.09-1.19 (6H, m), 2.80-3.10 (2H, m), 3.40-3.60 (1H,m), 4.16-4.41 (2H, m), 4.61-4.47 (2H, m), 5.06-5.10 (1H, m), 5.71(0.45H, d, J=7.5 Hz), 5.74 (0.55H, d, J=7.8 Hz), 6.60-6.72 (2H, m),6.86-6.94 (1H, m), 7.10-7.46 (6H, m).

Reference Example 283

¹H-NMR (CDCl₃) δ: 1.10-1.21 (6H, m), 2.75-2.86 (1H, m), 2.99-3.14 (1H,m), 4.23-4.37 (2H, m), 4.59-4.74 (2H, m), 5.04 (1H, s), 5.67-5.80 (1H,m), 6.58-6.67 (2H, m), 6.88-7.08 (1H, m), 7.11-7.38 (5H, m).

Reference Example 284

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.80(1H, ddd, J=4.5 Hz, 4.5 Hz, 9.9 Hz), 3.07 (1H, t, J=3.9 Hz, 13.2 Hz,13.2 Hz), 3.50 (1H, ddd, J=4.2 Hz, 4.2 Hz, 18.0 Hz), 4.24 (1H, 6.9 Hz),4.34 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.63-4.74 (2H, m), 5.06 (1H,s), 5.81 (1H, d, J=7.8 Hz), 6.57-6.64 (2H, m), 6.65 (1H, d, J=7.5 Hz),6.82 (1H, d, J=9.3 Hz), 6.90 (1H, ddd, J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.02(1H, dd, J=2.7 Hz, 9.0 Hz), 7.19-7.26 (2H, m).

Reference Example 285

First Step

Compound 285A (5.00 g, 29.3 mmol) was dissolved in dimethylformamide(150 ml), potassium carbonate (14.2 mmol) and iodoethane (7.11 ml, 88.0mmol) were added, and the mixture was stirred at room temperature for 2hours. To the reaction solution was added hexane, and the mixture waswashed with water and an aqueous saturated sodium chloride solution. Theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain a colorless oilysubstance 285B.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.2 Hz), 2.60 (3H, s), 4.37 (2H, q,J=7.1 Hz), 7.17 (1H, td, J=7.9, 0.6 Hz), 7.49 (1H, ddd, J=8.0, 1.4, 0.4Hz), 7.68 (1H, ddd, J=7.8, 1.4, 0.3 Hz).

Second Step

Compound 285B (5.63 g, 28.3 mmol) obtained in the first step wasdissolved in carbon tetrachloride (150 ml), N-bromosuccinimide (5.55 g,31.2 mmol) was added, and the mixture was stirred at 100° C. for 18hours. The reaction solution was cooled to room temperature, and washedwith water and an aqueous saturated sodium chloride solution. Theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain 8.08 g of an orange oilysubstance 285C.

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.6 Hz), 4.42 (2H, q, J=7.1 Hz), 5.10(2H, s), 7.31 (1H, t, J=8.6 Hz), 7.57 (1H, d, J=8.1 Hz), 7.84 (1H, d,J=8.1 Hz).

Third Step

Compound 285C (2.17 g, 7.8 mmol) obtained in the second step wasdissolved in acetone (25 ml), 4-fluorobenzenethiol (1.00 g, 7.80 mmol)and potassium carbonate (1.62 g, 11.7 mmol) were added, and the mixturewas stirred at 80° C. for 18 hours. After cooled to room temperature,the reaction solution was poured into water, the mixture was extractedwith ethyl acetate, the extract was washed with an aqueous saturatedsodium chloride solution, and the organic layer was dried with sodiumsulfate. The solvent was distilled off under reduced pressure, and theresulting crude product was purified by silica gel column chromatographyand eluted with n-hexane-ethyl acetate (4:1, v/v) to obtain 2.20 g of acolorless oily substance 285D.

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 4.25 (2H, d, J=7.5 Hz), 4.65(2H, s), 6.91 (2H, t, J=8.8 Hz), 7.19-7.31 (3H, m), 7.48 (1H, dd, J=8.2,1.4 Hz), 7.70 (1H, dd, J=7.6, 1.5 Hz).

Fourth Step

Compound 285D (2.20 g, 6.77 mmol) obtained in the third step wasdissolved in ethanol (20 ml), a 2N aqueous sodium hydroxide solution(16.9 ml, 33.8 mmol) was added, and the mixture was stirred at roomtemperature for 3 hours. To the reaction solution was added water, themixture was made acidic with dilute hydrochloric acid, and extractedwith ethyl acetate. The organic layer was washed with an aqueoussaturated sodium chloride solution, and dried with sodium sulfate, andthe solvent was distilled off under reduced pressure. To the resultingcompound was added n-hexane, and the precipitated residue was filteredto obtain 1.81 g of a white solid 285E.

¹H-NMR (CDCl₃) δ: 4.74 (2H, s), 6.95 (2H, t, J=8.8 Hz), 7.34 (3H, m),7.59 (1H, dd, J=7.9, 1.5 Hz), 7.92 (1H, dd, J=7.9, 1.3 Hz).

Fifth Step

To compound 285E (1.81 g, 6.10 mmol) obtained in the fourth step wasadded polyphosphoric acid (10.0 g), and the mixture was stirred at 120°C. for 5 hours. After cooled to room temperature, water was added, andthe mixture was extracted with ethyl acetate. The organic layer wasdried with sodium sulfate, the solvent was concentrated under reducedpressure, to the resulting compound were added n-hexane-ethyl acetate,and the precipitated residue was filtered to obtain 1.18 g of a whitesolid 285F.

¹H-NMR (CDCl₃) δ: 4.28 (2H, s), 7.18 (1H, ddd, J=9.3, 6.6, 2.3 Hz), 7.33(2H, m), 7.46 (1H, dd, J=7.7, 1.5 Hz), 7.59 (1H, dd, J=7.9, 1.3 Hz),7.91 (1H, dd, J=10.1, 2.9 Hz).

Sixth Step

To compound 285F (1.17 g, 4.20 mmol) was added methanol (15 ml), sodiumborohydride (191 mg, 5.04 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 2 hours. The reaction solution waspoured into water, the mixture was extracted with dichloromethane, theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 945 mg of a white solid 285G.

¹H-NMR (CDCl₃) δ: 2.58 (1H, d, J=3.2 Hz), 4.46 (1H, d, J=14.3 Hz), 4.58(1H, d, J=14.6 Hz), 6.33 (1H, d, J=3.7 Hz), 6.82 (1H, td, J=8.3, 2.9Hz), 7.07 (1H, dd, J=8.5, 5.4 Hz), 7.20 (1H, t, J=7.9 Hz), 7.33 (2H, m),7.44 (1H, d, J=6.9 Hz).

Seventh Step

According to the same procedure as that of Reference example 107,compound 285 was synthesized.

MS: m/z=486 [M+H]⁺

Using amines which are commercially available or known in the referencesand intermediates corresponding to compound 285A to compound 285G whichare commercially available or known in the references, and according tothe method of Reference example 285, compounds 286 to compound 359 weresynthesized.

Reference Example 286

MS: m/z=595 [M+H]⁺.

Reference Example 287

MS: m/z=475 [M+H]⁺.

Reference Example 288

¹H-NMR (DMSO-d₆) δ: 1.57 (1H, brs), 1.84-1.99 (2H, m), 2.68 (3H, d,J=4.6 Hz), 3.08-3.17 (2H, m), 3.39 (3H, brs), 3.89 (1H, d, J=13.4 Hz),4.16 (1H, d, J=13.3 Hz), 4.54 (1H, brs), 5.10 (1H, d, J=12.7 Hz), 5.50(1H, s), 5.63 (1H, d, J=13.4 Hz), 5.73 (1H, d, J=7.8 Hz), 6.82-7.94 (9H,m).

MS: m/z=489 [M+H]⁺.

Reference Example 289

MS: m/z=503 [M+H]⁺.

Reference Example 290

MS: m/z=505 [M+H]⁺.

Reference Example 291

MS: m/z=517 [M+H]⁺.

Reference Example 292

MS: m/z=503 [M+H]⁺.

Reference Example 293

MS: m/z=489 [M+H]⁺.

Reference Example 294

MS: m/z=456 [M+H]⁺.

Reference Example 295

MS: m/z=488 [M+H]⁺.

Reference Example 296

MS: m/z=498 [M+H]⁺

Reference Example 297

¹H-NMR (DMSO-d₆) δ: 3.21 (1H, m), 3.85 (1H, d, J=13.4 Hz), 4.08-4.18(3H, m), 4.28 (1H, d, J=13.4 Hz), 5.10 (1H, d, J=13.7 Hz), 5.45 (1H, s),5.57-5.64 (2H, m), 6.82-7.50 (10H, m).

MS: m/z=504 [M+H]⁺.

Reference Example 298

According to Reference example 107, compound 298 was synthesized by thesame procedure.

MS: m/z=452 [M+H]⁺.

Reference Example 299

MS: m/z=450 [M+H]⁺.

Reference Example 300

MS: m/z=464 [M+H]⁺.

Reference Example 301

¹H-NMR (DMSO-d₆) δ: 1.00 (3H, d, J=6.9 Hz), 1.06 (3H, d, J=6.9 Hz), 3.88(1H, d, J=13.4 Hz), 4.32 (1H, d, J=13.3 Hz), 4.67 (1H, m), 4.97 (1H, d,J=13.4 Hz), 5.43 (1H, s), 5.59 (2H, m), 6.84-7.45 (9H, m), 11.90 (1H,brs).

MS: m/z=434 [M+H]⁺.

Reference Example 302

¹H-NMR (DMSO-d₆) δ: 0.11 (1H, m), 0.54-0.92 (3H, m), 2.71 (1H, m), 3.85(1H, d, J=13.7 Hz), 4.06 (1H, d, J=13.1 Hz), 5.06 (1H, d, J=13.1 Hz),5.35 (1H, s), 5.57 (2H, m), 7.15 (9H, m), 11.66 (1H, brs).

MS: m/z=432 [M+H]⁺.

Reference Example 303

¹HNMR (CDCl₃) δ: 1.14 (1H, m), 1.54 (2H, m), 1.67 (1H, m), 3.60 (1H, d,J=13.5 Hz), 4.39 (1H, d, J=12.6 Hz), 5.02 (1H, s), 5.07 (1H, d, J=12.6Hz), 5.60 (1H, d. J=13.5 Hz), 5.77 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7Hz), 7.07-7.13 (3H, m), 7.25-7.44 (4H, m).

MS: m/z=457.10 [M+H]⁺.

Reference Example 304

¹H-NMR (DMSO-d₆) δ: 3.33-3.42 (1H, m), 3.84 (1H, d, J=13.1 Hz),3.90-4.10 (1H, m), 4.24 (1H, d, J=13.4 Hz), 4.35-4.66 (2H, m), 5.13 (1H,d, J=13.4 Hz), 5.43 (1H, s), 5.54-5.64 (2H, m), 6.80-6.95 (2H, m),7.04-7.50 (8H, m).

MS: m/z=438 [M+H]⁺.

Reference Example 305

MS: m/z=487 [M+H]⁺.

Reference Example 306

¹H-NMR (DMSO-d₆) δ: 3.69-3.82 (1H, m), 3.89 (1H, d, J=13.6 Hz), 4.40(1H, d, J=12.9 Hz), 4.60-4.77 (1H, m), 5.27 (1H, d, J=13.3 Hz), 5.43(1H, s), 5.60 (1H, d, J=13.6 Hz), 5.70 (1H, d, J=7.7 Hz), 6.84-6.95 (1H,m), 7.08-7.55 (9H, m).

MS: m/z=474 [M+H]⁺.

Reference Example 307

¹H-NMR (DMSO-d₆) δ: 3.81 (1H, d, J=13.5 Hz), 4.29 (1H, d, J=13.5 Hz),4.33 (1H, d, J=16.2 Hz), 4.96 (1H, d, J=16.2 Hz), 5.23 (1H, d, J=13.5Hz), 5.49 (1H, s), 5.59 (1H, d, J=13.2 Hz), 5.64 (1H, d, J=7.7 Hz),6.82-6.97 (2H, m), 7.05-7.41 (10H, m), 7.80 (1H, td, J=7.6, 1.7 Hz),8.47 (1H, d, J=4.9 Hz).

MS: m/z=483 [M+H]⁺.

Reference Example 308

¹H-NMR (DMSO-d₆) δ: 1.28 (9H, s), 3.86 (1H, d, J=13.6 Hz), 4.42 (1H, d,J=13.3 Hz), 4.99 (1H, d, J=13.4 Hz), 5.32 (1H, s), 5.53 (1H, d, J=13.3Hz), 5.60 (1H, d, J=7.6 Hz), 6.81-7.63 (10H, m).

MS: m/z=448 [M+H]⁺.

Reference Example 309

¹H-NMR (DMSO-d₆) δ: 1.03 (3H, t, J=7.4 Hz), 3.12-3.26 (1H, m), 3.43-3.58(1H, m), 3.85 (1H, d, J=13.6 Hz), 4.21 (1H, d, J=13.4 Hz), 5.07 (1H, d,J=13.4 Hz), 5.40 (1H, s), 5.57 (1H, d, J=13.1 Hz), 5.59 (1H, d, J=7.3Hz), 6.80-6.88 (1H, m), 6.91 (1H, d, J=7.9 Hz), 7.03-7.55 (8H, m).

MS: m/z=420 [M+H]⁺.

Reference Example 310

MS: m/z=498 [M+H]⁺.

Reference Example 311

¹H-NMR (CDCl₃) δ: 1.73-1.85 (2H, m), 2.96-3.07 (1H, m), 3.27 (3H, s),3.42 (2H, t, J=5.6 Hz), 3.56 (1H, d, J=13.5 Hz), 3.93-4.04 (1H, m), 4.25(1H, d, J=13.2 Hz), 4.95 (1H, d, J=12.9 Hz), 5.13 (1H, s), 5.65 (1H, d,J=13.2 Hz), 5.82 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7 Hz), 6.78-6.86(1H, m), 7.03-7.15 (3H, m), 7.17-7.47 (5H, m).

MS: m/z=464 [M+H]⁺.

Reference Example 312

¹H-NMR (CDCl₃) δ: 1.10 (3H, t, J=6.9 Hz), 2.79-2.91 (1H, m), 3.41 (2H,q, J=7.1 Hz), 3.46-3.69 (3H, m), 4.30 (1H, d, J=13.5 Hz), 5.01 (1H, d,J=13.5 Hz), 5.12 (1H, s), 5.65 (1H, d, J=13.5 Hz), 5.83 (1H, d, J=7.7Hz), 6.68 (1H, d, J=7.7 Hz), 6.77-6.86 (1H, m), 7.03-7.12 (3H, m),7.16-7.46 (5H, m).

MS: m/z=464 [M+H]⁺.

Reference Example 313

¹H-NMR (CDCl₃) δ: 1.30-1.47 (1H, m), 1.49-1.67 (1H, m), 1.73-2.02 (4H,m), 2.09-2.23 (2H, m), 3.60 (1H, d, J=13.5 Hz), 4.39 (1H, d, J=12.9 Hz),4.45-4.64 (1H, m), 4.93 (1H, d, J=12.6 Hz), 5.10 (1H, s), 5.65 (1H, d,J=13.5 Hz), 5.87 (1H, d, J=7.4 Hz), 6.67 (1H, d, J=8.0 Hz), 6.76-6.85(1H, m), 7.08 (2H, d, J=3.8 Hz), 7.16 (2H, d, J=7.7 Hz), 7.23-7.31 (1H,m), 7.34-7.48 (2H, m).

MS: m/z=510 [M+H]⁺.

Reference Example 314

MS: m/z=476 [M+H]⁺.

Reference Example 315

MS: m/z=488 [M+H]⁺.

Reference Example 316

¹H-NMR (DMSO-d₆) δ: 3.83 (1H, d, J=13.4 Hz), 4.34 (1H, d, J=13.1 Hz),4.67 (1H, d, J=15.9 Hz), 5.05 (1H, d, J=15.9 Hz), 5.20 (1H, d, J=13.4Hz), 5.33 (1H, s), 5.60 (1H, d, J=13.8 Hz), 5.64 (1H, d, J=7.8 Hz), 6.87(3H, m), 7.05-7.19 (4H, m), 7.35-7.44 (2H, m), 7.74 (1H, d, 3.3 Hz),7.77 (1H, d, 3.3 Hz).

Reference Example 317

MS: m/z=464 [M+H]⁺

Reference Example 318

MS: m/z=494 [M+H]⁺

Reference Example 319

¹H-NMR (CDCl₃) δ: 3.18-3.35 (1H, m), 3.60 (1H, d, J=13.7 Hz), 4.37 (1H,d, J=13.2 Hz), 4.75-4.95 (1H, m), 5.07-5.15 (2H, m), 5.60 (1H, d, J=13.7Hz), 5.85 (1H, d, J=7.7 Hz), 6.68 (1H, d, J=7.7 Hz), 6.79-6.88 (1H, m),7.09-7.14 (3H, m), 7.16 (1H, d, J=7.7 Hz), 7.29-7.36 (1H, m), 7.36-7.41(1H, m), 7.42-7.50 (1H, m).

MS: m/z=524 [M+H]⁺.

Reference Example 320

¹H-NMR (CDCl₃) δ: 0.89 (9H, s), 0.97 (3H, d, J=7.1 Hz), 3.61 (1H, d,J=13.2 Hz), 4.43 (1H, d, J=13.2 Hz), 4.84-4.92 (2H, m), 5.11 (1H, s),5.70 (1H, d, J=13.2 Hz), 5.83 (1H, d, J=7.7 Hz), 6.72 (1H, d, J=7.4 Hz),6.79-6.85 (1H, m), 7.03-7.09 (2H, m), 7.16-7.24 (3H, m), 7.29-7.44 (2H,m).

MS: m/z=476 [M+H]⁺.

Reference Example 321

¹H-NMR (CDCl₃) δ: 2.87 (0.75H, s), 3.01 (2.25H, s), 3.55 (1.5H, d,J=10.2 Hz), 3.62 (0.5H, 13.5 Hz), 4.17 (0.5H, d, J=13.2 Hz), 4.22 (1.5Hz, J=12.9 Hz), 4.97 (1H, d, J=12.9 Hz), 5.02 (0.25H, s), 5.11 (0.75H,s), 5.63 (0.75H, d, J=13.5 Hz), 5.77-5.83 (1.25H, m), 6.64-6.68 (1H, m),6.76-6.85 (1H, m), 7.01 (1H, d, J=7.5 Hz), 7.05-7.13 (2H, m), 7.17-7.45(3H, m).

Reference Example 322

¹H-NMR (CDCl₃) δ: 3.63 (1H, d, J=13.4 Hz), 4.51-4.59 (2H, m), 4.68-4.98(4H, m), 5.13 (1H, d, J=12.9 Hz), 5.28 (1H, s), 5.71 (1H, d, J=13.3 Hz),5.85 (1H, d, J=7.7 Hz), 6.77 (1H, d, J=7.4 Hz), 6.82-6.89 (1H, m), 7.12(2H, d, J=3.5 Hz), 7.24 (1H, d, J=7.6 Hz), 7.33 (2H, d, J=4.4 Hz), 7.39(1H, d, J=7.1 Hz), 7.42-7.50 (1H, m).

MS: m/z=470 [M+H]⁺.

Reference Example 323

MS: m/z=450 [M+H]⁺

Reference Example 324

MS: m/z=482 [M+H]⁺

Reference Example 325

¹H-NMR (DMSO-d₆) δ: 1.93 (3H, s), 3.13 (1H, m), 3.86 (1H, d, J=13.6 Hz),4.06 (3H, m), 4.26 (1H, d, J=13.3 Hz), 5.14 (1H, d, J=13.6 Hz), 5.44(1H, s), 5.60 (2H, m), 6.82-7.49 (10H, m).

MS: m/z=478 [M+H]⁺.

Reference Example 326

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.6 Hz), 1.10 (3H, d, J=6.9 Hz), 3.70(1H, d, J=13.5 Hz), 4.37 (1H, d, J=12.9 Hz), 4.75-4.85 (2H, m), 5.18(1H, s), 5.76 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.8 Hz), 6.67 (1H, dd,J=1.2 Hz, 7.8 Hz), 6.77 (1H, t, J=7.8 Hz), 7.07 (1H, d, J=7.5 Hz),7.18-7.30 (3H, m), 7.35-7.46 (2H, m).

Reference Example 327

¹H-NMR (CDCl₃) δ: 1.06 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=7.2 Hz), 3.60(H, d, J=13.5 Hz), 4.36 (1H, d, J=12.9 Hz), 4.75-4.83 (2H, m), 5.10 (1H,s), 5.67 (1H, d, J=13.2 Hz), 5.86 (1H, d, J=7.5 Hz), 6.65 (1H, d, J=8.1Hz), 6.78 (1H, dd, J=1.8 Hz, 8.1 Hz), 7.08-7.18 (2H, m), 7.13 (1H, d,J=8.1 Hz), 7.24-7.30 (1H, m), 7.33-7.36 (1H, m), 7.39-7.45 (1H, m).

Reference Example 328

¹H-NMR (CDCl₃) δ: 0.98 (0.4H, d, J=7.2 Hz), 1.07 (2.6H, d, J=6.6 Hz),1.15 (2.6H, d, J=6.9 Hz), 1.27 (0.4H, d, J=0.6 Hz), 3.62 (0.9H, d,J=13.2 Hz), 3.73 (0.1H, d, J=13.8 Hz), 4.36 (1H, d, J=12.9 Hz),4.77-4.88 (1H, m), 4.83 (1H, d, J=12.9 Hz), 5.07 (1H, s), 5.62 (1H, d,J=13.2 Hz), 5.77 (0.1H, d, J=7.5 Hz), 5.85 (0.9H, d, J=7.8 Hz),6.69-6.83 (1H, m), 6.98-7.07 (2H, m), 7.18 (2H, d, J=7.8 Hz), 7.25-7.35(2H, m), 7.40-7.45 (1H, m).

Reference Example 329

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.6 Hz), 1.15 (3H, d, J=6.9 Hz), 3.63(1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.77-4.8 (1H, m), 4.82 (1H,d, J=12.6 Hz), 5.06 (1H, s), 5.60 (1H, d, J=12.9 Hz), 5.85 (1H, d, J=7.8Hz), 6.53 (1H, dd, J=3.0 Hz, 9.0 Hz), 6.80-6.86 (1H, m), 7.03 (1H, dd,J=4.2 Hz, 9.0 Hz), 7.16-7.30 (3H, m), 7.35 (1H, d, J=6.3 Hz), 7.40-7.45(1H, m).

Reference Example 330

¹H-NMR (DMSO-d₆) δ: 1.02 (3H, t, J=7.2 Hz), 3.07-3.22 (1H, m), 3.44-3.59(1H, m), 4.00 (1H, d, J=13.4 Hz), 4.21 (1H, d, J=13.4 Hz), 5.06 (1H, d,J=13.3 Hz), 5.47-5.76 (3H, m), 6.84-6.92 (1H, m), 6.92-6.99 (1H, m),7.04 (1H, d, J=7.6 Hz), 7.10-7.52 (6H, m).

MS: m/z=454 [M+H]⁺.

Reference Example 331

¹H-NMR (CDCl₃) δ: 2.96 (0.79H, s), 3.00 (2.2H, s), 3.59 (0.75H, d,J=13.2 Hz), 3.62 (0.25H, d, J=13.8 Hz), 4.15 (0.25H, d, J=13.2 Hz), 4.21(0.75H, d, J=12.9 Hz), 4.95-5.01 (2H, m), 5.07 (1H, s), 5.56 (1H, d,J=13.5 Hz), 5.75-5.79 (1H, m), 5.88 (1H, d, J=7.8 Hz), 6.63 (0.36H, d,J=7.8 Hz), 6.73 (1H, d, J=1.8 Hz), 6.83 (0.39H, d, J=7.2 Hz), 7.01-7.46(7.25H, m).

Reference Example 332

MS: m/z=484 [M+H]⁺

Reference Example 333

MS: m/z=484 [M+H]⁺.

Reference Example 334

¹H-NMR (DMSO-d₆) δ: 3.01-3.10 (1H, m), 3.16 (3H, s), 3.40 (2H, m), 3.89(2H, d, J=13.4 Hz), 4.19 (1H, d, J=13.4 Hz), 5.06 (1H, d, J=13.6 Hz),5.49 (1H, s), 5.58 (1H, d, J=13.4 Hz), 5.70 (1H, d, J=7.8 Hz), 6.89-7.48(8H, m), 11.36 (1H, s).

Reference Example 335

¹H-NMR (DMSO-d₆) δ: 3.00-3.09 (1H, m), 3.15 (3H, s), 3.39 (2H, m), 3.94(1H, m), 4.00 (1H, d, J=13.2 Hz), 4.20 (1H, d, J=13.4 Hz), 5.06 (1H, d,J=13.4 Hz), 5.54 (1H, s), 5.65 (2H, m), 6.86-7.50 (8H, m), 11.54 (1H,brs).

Reference Example 336

¹H-NMR (DMSO-d₆) δ: 3.01-3.09 (1H, m), 3.15 (3H, s), 3.40 (2H, m),3.87-3.94 (1H, m), 3.98 (1H, d, J=13.6 Hz), 4.20 (1H, d, J=13.6 Hz),5.06 (1H, d, J=13.4 Hz), 5.54 (1H, s), 5.62 (1H, d, J=13.6 Hz), 5.67(1H, d, J=7.6 Hz), 6.78-7.50 (8H, m).

MS: m/z=468 [M+H]⁺

Reference Example 337

¹H-NMR (DMSO-d₆) δ: 3.07 (1H, m), 3.16 (3H, s), 3.41 (2H, s), 3.89 (1H,d, J=13.7 Hz), 3.91 (1H, m), 4.19 (1H, d, J=13.6 Hz), 5.06 (1H, d,J=13.6 Hz), 5.48 (1H, s), 5.61 (1H, d, J=13.3 Hz), 5.69 (1H, d, J=7.6Hz), 6.70-7.48 (9H, m).

MS: m/z=468 [M+H]⁺

Reference Example 338

MS: m/z=468 [M+H]⁺

Reference Example 339

¹H-NMR (DMSO-d₆) δ: 3.14 (3H, s), 3.18 (s, 3H), 3.50 (4H, m), 4.00 (1H,d, J=13.1 Hz), 4.49 (1H, d, J=13.3 Hz), 4.77 (1H, m), 4.95 (1H, d,J=13.3 Hz), 5.56 (1H, s), 5.68 (2H, m), 7.14 (8H, m).

MS: m/z=512 [M+H]⁺

Reference Example 340

¹H-NMR (DMSO-d₆) δ: 3.12 (3H, s), 3.20 (3H, s), 3.51 (4H, m), 3.96 (1H,d, J=13.3 Hz), 4.53 (1H, d, J=13.4 Hz), 4.75 (1H, m), 4.97 (1H, d,J=13.1 Hz), 5.50 (1H, d, J=13.3 Hz), 5.54 (1H, s), 5.67 (1H, d, J=7.8Hz), 6.87-7.54 (8H, m).

MS: m/z=530 [M+H]⁺

Reference Example 341

MS: m/z=466 [M+H]⁺

Reference Example 342

MS: m/z=506 [M+H]⁺

Reference Example 343

MS: m/z=522 [M+H]⁺

Reference Example 344

MS: m/z=506 [M+H]⁺

Reference Example 345

MS: m/z=506 [M+H]⁺

Reference Example 346

MS: m/z=470 [M+H]⁺

Reference Example 347

¹H-NMR (CDCl₃) δ: 2.88 (0.60H, s), 2.99 (2.40H, s), 3.67 (0.80H, d,J=13.8 Hz), 3.73 (0.20H, d, J=14.1 Hz), 4.16 (0.20H, d, J=11.1 Hz), 4.20(0.80H, d, J=12.9 Hz), 4.97 (0.80H, d, J=12.9 Hz), 4.99 (0.20H, d, J=15Hz), 5.10 (0.20H, s), 5.18 (0.80H, s), 5.69 (0.80H, d, J=13.5 Hz), 5.79(0.20H, d, J=7.8 Hz), 5.85 (0.80H, d, J=7.5 Hz), 5.88 (0.20H, J=13.5Hz), 6.62-6.66 (1H, m), 6.75-6.85 (1H, m), 6.98 (1H, d, J=7.5 Hz),7.03-7.16 (0.5H, m), 7.19 (1H, d, J=6.9 Hz), 7.24-7.39 (2.5H, m),7.43-7.48 (1H, m).

Reference Example 348

¹H-NMR (CDCl₃) δ: 2.91 (0.75H, s), 2.99 (2.25H, s), 3.57 (0.75H, d,J=13.8 Hz), 3.63 (0.25H, d, 13.8 Hz), 4.17 (0.25H, d, J=12.9 Hz), 4.10(0.75H, d, J=12.9 Hz), 4.99 (0.75H, d, J=12.9 Hz), 5.00 (0.25H, s), 5.01(0.25H, d, J=12.3 Hz), 5.10 (0.75H, s), 5.61 (0.75H, d, J=13.5 Hz), 5.78(0.25H, J=7.5 Hz), 5.80 (0.25H, J=15 Hz), 5.89 (0.75H, d, J=7.5 Hz),6.60 (0.75H, d, J=8.4 Hz), 6.64 (0.25H, d, J=7.8 Hz), 6.78 (1H, dd,J=2.1 Hz, 8.1 Hz), 7.03 (1H, d, J=7.8 Hz), 7.04-7.21 (2H, m), 7.26-7.36(2H, m), 7.41-7.47 (1H, m).

Reference Example 349

¹H-NMR (CDCl₃) δ: 2.94 (0.66H, s), 3.00 (2.34H, s), 3.60 (0.78H, d,J=13.5 Hz), 3.65 (0.22H, d, J=3.8 Hz), 4.22 (1H, d, J=12.9 Hz),4.94-5.00 (1H, m), 5.06 (1H, s), 5.54 (0.78H, d, J=13.2 Hz), 5.71(0.22H, d, J=13.8 Hz), 5.78 (0.22H, d, J=7.5 Hz), 5.88 (0.78H, d, J=7.8Hz), 6.49 (1H, dd, J=3.0 Hz, 9.0 Hz), 6.66 (0.22H, d, J=7.8 Hz),6.82-6.88 (1H, m), 6.97-7.13 (2H, m), 7.16-7.21 (1H, m), 7.29-7.36 (2H,m), 7.41-7.46 (1H, m).

Reference Example 350

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.63(1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.6 Hz), 4.78-4.87 (1H, m), 5.10(1H, s), 5.67 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.8 Hz), 6.65 (1H, d,J=2.1 Hz), 6.96-6.99 (1H, m), 7.08-7.12 (2H, m), 7.17 (1H, d, J=13.5Hz), 7.25-7.32 (1H, m), 7.35-7.37 (1H, m), 7.42-7.47 (1H, m).

Reference Example 351

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.68(1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.76-4.84 (2H, m), 5.18(1H, s), 5.72 (1H, d, J=13.5 Hz), 5.81 (1H, dd, J=0.9 Hz, 7.5 Hz), 6.56(1H, d, J=7.2 Hz), 6.76-6.83 (1H, m), 6.90 (1H, t, J=9.0 Hz), 7.07-7.11(1H, m), 7.19 (1H, d, J=7.5 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m).

Reference Example 352

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=7.1 Hz), 3.59(1H, d, J=13.2 Hz), 4.36 (1H, d, J=9.9 Hz), 4.75-4.85 (2H, m), 5.11 (1H,s), 5.70 (1H, d, J=13.2 Hz), 5.84 (1H, d, J=7.8 Hz), 6.48-6.55 (1H, m),6.71 (1H, dd, J=5.4 Hz, 8.4 Hz), 6.80 (1H, dd, J=2.4 Hz, 9.3 Hz), 7.11(1H, d, J=7.8 Hz), 7.18 (1H, dd, J=0.9 Hz), 7.5 Hz), 7.25-7.30 (1H, m),7.32-7.36 (1H, m), 7.39-7.45 (1H, m).

Reference Example 353

¹H-NMR (CDCl₃) δ: 2.92 (0.66H, s), 3.01 (2.34H, s), 3.59 (0.78H, d,J=13.5 Hz), 3.67 (0.22H, d, J=13.8 Hz), 4.18 (0.22H, d, J=13.2 Hz), 4.21(0.78H, d, J=12.9 Hz), 5.03 (1H, J=12.9 Hz), 5.05 (0.22H, s), 5.10(0.78H, s), 5.62 (0.78H, d, J=13.5 Hz), 5.76-5.82 (0.44H, m), 5.87(0.78H, d, J=7.8 Hz), 6.62 (0.78H, brs), 6.68 (0.22H, d, J=8.1 Hz), 6.85(0.22H, d, J=7.8 Hz), 6.98-7.04 (1.56H, m), 7.11-7.39 (3H, m), 7.44-7.49(1H, m).

Reference Example 354

¹H-NMR (CDCl₃) δ: 2.89 (0.48H, s), 3.00 (2.52H, s), 3.64 (0.84H, d,J=13.5 Hz), 3.71 (0.16H, d, J=13.8 Hz), 4.21 (1H, d, J=12.9 Hz), 4.94(0.84H, d, J=12.9 Hz), 4.98 (0.16H, d, J=12.9 Hz), 5.10 (0.16H, s), 5.19(0.84H, s), 5.65 (0.84H, d, J=7.5 Hz), 5.77-5.85 (1.32H, m), 6.52(0.84H, d, J=7.8 Hz), 6.64 (0.16H, d, J=7.8 Hz), 6.77-6.84 (1H, m),6.89-6.95 (1H, m), 6.99 (1H, d, J=7.8 Hz), 7.07-7.25 (1H, m), 7.29-7.38(2H, m), 7.42-7.47 (1H, m).

Reference Example 355

¹H-NMR (CDCl₃) δ: 2.91 (0.48H, s), 3.00 (2.52H, s), 3.56 (d, J=13.8 Hz),3.62 (0.16H, d, J=13.8 Hz), 4.18 (0.16H, d, J=12.9 Hz), 4.20 (0.84H, d,J=12.9 Hz), 4.96 (0.84H, d, J=12.9 Hz), 4.98 (0.16H, d, J=13.8 Hz), 5.03(0.16H, s), 5.12 (0.84H, s), 5.64 (0.84H, d, J=13.5 Hz), 5.78-5.87(0.32H, m), 5.89 (0.84H, d, J=7.8 Hz), 6.50-6.56 (0.84H, m), 6.63-6.69(1.16H, m), 6.84 (1H, dd, J=2.4 Hz, 9.3 Hz), 6.94-6.97 (0.16H, m), 7.02(0.84H, d, J=7.5 Hz), 7.13-7.23 (1H, m), 7.33-7.38 (2H, m), 7.42-7.47(1H, m).

Reference Example 356

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=6.9 Hz), 2.24(3H, s), 3.68 (1H, d, J=13.2 Hz), 4.38 (1H, d, J=13.2 Hz), 4.76-4.85(1H, m), 4.80 (1H, d, J=12.6 Hz), 5.14 (1H, s), 5.72 (1H, d, J=12.9 Hz),5.76 (1H, d, J=7.8 Hz), 6.59 (1H, d, J=7.5 Hz), 6.72 (1H, t, J=7.5 Hz),6.99 (1H, d, J=6.9 Hz), 7.07 (1H, d, J=7.8 Hz), 7.17-7.27 (2H, m),7.33-7.42 (2H, m).

Reference Example 357

¹H-NMR (CDCl₃) δ: 1.10 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.58(1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.76-4.87 (1H, m), 4.85(1H, d, J=12.6 Hz), 5.06 (1H, s), 5.65 (1H, d, J=13.2 Hz), 5.79 (1H, d,J=7.5 Hz), 6.54 (1H, s), 6.89 (1H, dd, J=1.5 Hz, 8.4 Hz), 6.95 (1H, d,J=7.8 Hz), 7.14-7.19 (1H, m), 7.22-7.28 (1H, m), 7.33-7.43 (2H, m).

Reference Example 358

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 2.20(3H, s), 2.23 (3H, s), 3.77 (1H, d, J=12.6 Hz), 4.47 (1H, d, J=12.9 Hz),4.78-4.86 (1H, m), 4.88 (1H, 12.9 Hz), 5.49 (1H, d, J=12.9 Hz), 5.83(1H, d, J=11.1 Hz), 5.85 (1H, d, J=9.0 Hz), 6.64 (1H, d, J=7.8 Hz), 6.86(1H, J=7.8 Hz), 7.16-7.40 (5H, m).

Reference Example 359

¹H-NMR (DMSO-d₆) δ: 1.94 (3H, s), 3.07 (1H, m), 3.98-4.12 (4H, m), 4.25(2H, d, J=13.4 Hz), 5.13 (2H, d, J=13.3 Hz), 5.56 (1H, s), 5.66 (1H, d,J=13.5 Hz), 5.68 (1H, t, J=7.8 Hz), 6.87-7.51 (8H, m).

Reference Example 360

Compound 325 (46.0 mg, 0.0960 mmol) was dissolved in methanol (0.5 ml)and tetrahydrofuran (0.5 ml), a 2N aqueous sodium hydroxide solution(0.241 ml, 0.482 mmol) was added, and the mixture was stirred for 30minutes. To the reaction solution was added dilute hydrochloric acid tomake the solution acidic, and the mixture was extracted with chloroform.The organic layer was dried with sodium sulfate, and the reactionsolution was concentrated under reduced pressure. To the resultingcompound 360 were added n-hexane-diethyl ether, and the precipitatedresidue was filtered to obtain 33 mg of a white solid.

¹H-NMR (DMSO-d₆) δ: 2.85-2.94 (1H, m), 3.52 (2H, m), 3.89 (1H, d, J=13.4Hz), 3.98 (1H, td, J=9.1, 4.5 Hz), 4.24 (1H, d, J=13.6 Hz), 4.84 (1H,brs), 5.16 (1H, d, J=13.6 Hz), 5.48 (1H, s), 5.65 (2H, m), 6.86-7.55(9H, m).

MS: m/z=436 [M+H]⁺

Using ester bodies synthesized according to Reference examples 107, 246and 285, and according to the method of Reference example 320, compounds361 to 382 were synthesized.

Reference Example 361

¹H-NMR (DMSO-d₆) δ: 2.82 (3H, m), 3.49 (1H, brs), 3.71 (1H, dt, J=16.7,5.0 Hz), 4.03 (1H, t, J=7.8 Hz), 4.08-4.15 (2H, m), 4.79 (1H, brs), 5.01(1H, d, J=13.4 Hz), 5.25 (1H, s), 5.51 (1H, d, J=7.6 Hz), 6.72-7.41 (9H,m).

Reference Example 362

MS: m/z=432 [M+H]⁺.

Reference Example 363

MS: m/z=450 [M+H]⁺.

Reference Example 364

MS: m/z=448 [M+H]⁺.

Reference Example 365

MS: m/z=466 [M+H]⁺.

Reference Example 366

MS: m/z=466 [M+H]⁺.

Reference Example 367

MS: m/z=512 [M+H]⁺.

Reference Example 368

MS: m/z=406 [M+H]⁺.

Reference Example 369

MS: m/z=420 [M+H]⁺.

Reference Example 370

¹H-NMR (CDCl₃) δ: 1.23 (3H, s), 1.24 (3H, s), 2.43 (1H, d, J=13.7 Hz),2.81-2.91 (1H, m), 2.96-3.10 (1H, m), 3.61-3.72 (1H, m), 4.02-4.14 (1H,m), 4.15 (1H, d, J=13.7 Hz), 4.42 (1H, d, J=14.0 Hz), 4.95 (1H, s), 5.15(1H, d, J=13.5 Hz), 5.74 (1H, d, J=7.7 Hz), 6.54-6.61 (2H, m), 6.86-6.94(1H, m), 7.11-7.39 (8H, m).

MS: m/z=446 [M+H]⁺.

Reference Example 371

¹H-NMR (CDCl₃) δ: 1.24 (3H, s), 1.26 (3H, s), 2.52 (1H, d, J=14.0 Hz),3.56 (1H, d, J=13.7 Hz), 4.34 (1H, d, J=13.5 Hz), 4.36 (1H, d, J=13.5Hz), 5.04 (1H, s), 5.23 (1H, d, J=13.7 Hz), 5.63 (1H, d, J=13.5 Hz),5.84 (1H, d, J=7.7 Hz), 6.65 (1H, d, J=7.7 Hz), 6.76-6.84 (1H, m),7.03-7.18 (5H, m), 7.27-7.47 (4H, m).

MS: m/z=464 [M+H]⁺.

Reference Example 372

¹H-NMR (CDCl₃) δ: 1.21-1.68 (1H, m), 2.47 (1H, d, J=13.7 Hz), 3.55 (1H,d, J=13.5 Hz), 4.34 (1H, d, J=13.6 Hz), 4.35 (1H, d, J=13.6 Hz), 5.03(1H, s), 5.25 (1H, d, J=13.5 Hz), 5.63 (1H, d, J=13.5 Hz), 5.79 (1H, d,J=7.7 Hz), 6.64 (1H, d, J=7.4 Hz), 6.76-6.84 (1H, m), 7.03 (1H, d, J=7.7Hz), 7.06-7.10 (2H, m), 7.15 (1H, d, J=7.1 Hz), 7.28-7.37 (2H, m),7.37-7.46 (1H, m).

MS: m/z=504 [M+H]⁺.

Reference Example 373

MS: m/z=450 [M+H]⁺.

Reference Example 374

MS: m/z=492 [M+H]⁺.

Reference Example 375

MS: m/z=445 [M+H]⁺.

Reference Example 376

MS: m/z=512 [M+H]⁺.

Reference Example 377

MS: m/z=492 [M+H]⁺.

Reference Example 378

MS: m/z=478 [M+H]⁺

Reference Example 379

MS: m/z=478 [M+H]⁺

Reference Example 380

MS: m/z=492 [M+H]⁺

Reference Example 381

MS: m/z=492 [M+H]⁺

Reference Example 382

¹H-NMR (DMSO-d₆) δ: 2.76-2.85 (1H, m), 3.58 (2H, m), 3.92 (1H, m), 3.98(1H, d, J=13.5 Hz), 4.18 (1H, d, J=13.6 Hz), 4.80 (1H, brs), 5.10 (1H,t, J=8.8 Hz), 5.50-5.68 (3H, m), 6.87-7.52 (8H, m).

Reference Example 383

First Step

Compound 383A (1.00 g, 4.42 mmol) was dissolved in dichloromethane (50ml), mCPBA (2.67 g, 15.5 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 4 hours. To the reaction solution wasadded an aqueous sodium sulfite solution, and the mixture was extractedwith dichloromethane. The organic layer was washed with an aqueoussodium bicarbonate solution, and dried with sodium sulfate, and thesolvent was distilled off. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 1.06 g of a white solid 383B.

¹H-NMR (CDCl₃) δ: 4.81 (2H, s), 7.29-8.12 (6H, m).

Second Step

To compound 383B (1.05 g, 4.07 mmol) was added methanol (11 ml), sodiumborohydride (185 mg, 4.88 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 30 minutes. The reaction solution waspoured into water, the mixture was extracted with dichloromethane, theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 1.01 g of a white solid 383C.

¹H-NMR (CDCl₃) δ: 2.84 (1H, d, J=3.7 Hz), 4.76 (1H, d, J=14.6 Hz), 5.25(1H, d, J=14.6 Hz), 6.23 (1H, d, J=3.7 Hz), 7.28-7.96 (8H, m).

Third Step

According to Reference example 107, compound 383 was synthesized by thesame procedure.

MS: m/z=466 [M+H]⁺.

Using intermediates corresponding to 383A to 383C which are commerciallyavailable or known in the references, and according to the method ofReference example 383, compounds 384 to 389 were synthesized.

Reference Example 384

¹H-NMR (CDCl₃) δ: 1.12-1.25 (6H, m), 2.87-3.26 (3H, m), 3.42-3.67 (1H,m), 4.00-4.08 (1H, m), 4.28-4.35 (1H, m), 4.56-4.83 (3H, m), 5.10-5.30(1H, m), 5.89-6.11 (1H, m), 6.55-6.63 (0.5H, m), 6.71-6.75 (0.5H, m),6.84-6.94 (1H, m), 7.03-7.47 (4H, m), 8.18-8.20 (0.5H, m), 8.48-8.49(0.5H, m).

Reference Example 385

¹H-NMR (CDCl₃) δ: 0.59 (3H, d, J=6.6 Hz), 1.07-1.14 (4H, m), 1.19-1.28(1H, m), 2.22-2.32 (1H, m), 2.73-3.12 (3H, m), 4.71-4.81 (1H, m), 4.83(1H, d, J=12.9 Hz), 4.96 (1H, d, J=12.9 Hz), 5.88 (1H, d, J=7.5 Hz),5.89 (1H, s), 6.89 (1H, m), 7.00-7.04 (2H, m), 7.08-7.18 (2H, m),7.22-7.27 (1H, m), 7.38 (1H, d, J=7.5 Hz), 7.58-7.61 (1H, m), 7.79 (1H,d, J=7.5 Hz).

Reference Example 386

¹H-NMR (CDCl₃) δ: 0.95 (3H, d, J=6.9 Hz), 1.17 (3H, d, 6.9 Hz), 3.34(2H, d, J=12.3 Hz), 4.39 (1H, d, J=12.9 Hz), 4.56-4.65 (1H, m), 4.85(1H, d, J=12.9 Hz), 4.93 (1H, m), 5.77 (1H, d, J=7.5 Hz), 6.77-6.81 (1H,m), 6.79 (1H, d, J=7.5 Hz), 7.00-7.05 (1H, m), 7.21-7.29 (2H, m),7.32-7.42 (3H, m).

Reference Example 387

¹H-NMR (CDCl₃) δ: 1.06-1.17 (6H, m), 4.02-4.17 (1H, m), 4.61-4.78 (2H,m), 5.16 (1H, d, J=5.1 Hz), 5.72 (1H, t, J=8.1 Hz), 6.54 (0.5H, d, J=7.8Hz), 6.84 (0.5H, d, J=7.8 Hz), 6.91-7.08 (2H, m), 7.16-7.47 (4H, m),7.56-7.59 (1H, m), 8.00 (0.5H, J=6.3 Hz), 8.09-8.12 (0.5H, m), 8.51(0.5H, s), 8.68 (0.5H, s).

Reference Example 388

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=6.9 Hz), 1.25 (3H, d, J=6.9 Hz),2.76-2.91 (2H, m), 3.23-3.31 (1H, m), 4.17-4.33 (2H, m), 4.54-4.84 (2H,m), 5.18 (1H, s), 5.87 (1H, d, J=7.8 Hz), 6.70 (1H, d, J=5.1 Hz), 6.86(1H, d, J=7.8 Hz), 7.04 (1H, d, J=5.1 Hz), 7.19-7.25 (2H, m), 7.32-7.38(2H, m).

Reference Example 389

¹H-NMR (DMSO-d₆) δ: 1.04-1.20 (6H, m), 2.83-3.02 (1H, m), 3.46-3.57 (1H,m), 3.75-3.85 (1H, m), 4.13-4.26 (1H, m), 4.32-4.50 (1H, m), 4.56-4.62(1H, m), 4.89 (1H, d, J=13.2 Hz), 5.36 (1H, s), 5.44-5.50 (1H, m), 6.73(1H, d, J=7.8 Hz), 6.86 (1H, t, J=7.5 Hz), 6.95-6.98 (1H, m), 7.09-6.54(5H, m).

Reference Example 390

First Step

Compound 390A (14.8 g, 115 mmol) was added to methanol (200 ml), sodiummethoxide (28% methanol solution, 22.2 g, 115 mmol) was added at roomtemperature, and the mixture was stirred for 1 hour. The solvent wasdistilled off under reduced pressure to obtain 17.3 g of a white solid.To 5.61 g of it was added phthalide (5.00 g, 37.3 mmol), and the mixturewas stirred at 200° C. for 1 hour. The reaction solution was poured intowater, the mixture was made acidic with hydrochloric acid, and thegenerated white precipitate was filtered. This was dissolved inchloroform, the solution was dried with sodium sulfate, and the solventwas distilled off. To the resulting compound were addedn-hexane-chloroform-diisopropyl ether, and the precipitated residue wasfiltered to obtain 2.44 g of a pale brown solid 390B.

¹H-NMR (CDCl₃) δ: 5.61 (2H, s), 6.92 (1H, td, J=7.6, 1.4 Hz), 7.01 (1H,dd, J=8.3, 1.3 Hz), 7.21 (1H, ddd, J=8.7, 7.0, 1.2 Hz), 7.32-7.54 (2H,m), 7.66 (1H, td, J=7.6, 1.4 Hz), 7.92-7.99 (1H, m), 8.17 (1H, dd,J=7.9, 1.3 Hz).

Second Step

Compound 390B (2.44 g, 9.29 mmol) was dissolved in dichloromethane (30ml), trifluoroacetic anhydride (1.44 ml, 10.2 mmol) and borontrifluoride etherate (0.235 ml, 1.86 mmol) were added, and the mixturewas stirred at room temperature for 3 hours. The reaction solution waspoured into water, the mixture was extracted with dichloromethane, theorganic layer was washed with 1N hydrochloric acid and an aqueoussaturated sodium chloride solution, and the solvent was distilled off.The resulting crude product was purified by silica gel columnchromatography, and eluted with n-hexane-ethyl acetate (4:1, v/v) toobtain 1.76 g of a pale yellow solid 390C.

¹H-NMR (CDCl₃) δ: 5.36 (2H, s), 7.11 (1H, t, J=8.0 Hz), 7.43-7.66 (4H,m), 7.93 (1H, d, J=6.5 Hz), 8.19 (1H, dd, J=8.1, 1.8 Hz).

Third Step

To compound 390C (1.76 g, 7.19 mmol) was added methanol (20 ml), sodiumborohydride (327 mg, 8.63 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 30 minutes. The reaction solution waspoured into water, the mixture was extracted with dichloromethane, theorganic layer was dried with sodium sulfate, and the solvent wasdistilled off. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 1.44 g of a white solid 390D.

¹H-NMR (CDCl₃) δ: 2.75 (1H, d, J=5.0 Hz), 5.18 (1H, d, J=13.6 Hz), 5.69(1H, d, J=5.0 Hz), 5.89 (1H, d, J=13.6 Hz), 6.93 (1H, t, J=7.9 Hz),7.19-7.43 (6H, m).

Fourth Step

According to the same procedure as that of Reference example 107,compound 390 was synthesized.

MS: m/z=452 [M+H]⁺

Using amines which are commercially available or known in the referencesand intermediates corresponding to 390A to 390D which are commerciallyavailable or known in the references, and according to the method ofReference example 390, compounds 391 to 412 were synthesized.

Reference Example 391

MS: m/z=416 [M+H]⁺.

Reference Example 392

MS: m/z=416 [M+H]⁺.

Reference Example 393

MS: m/z=458 [M+H]⁺.

Reference Example 394

MS: m/z=434 [M+H]⁺.

Reference Example 395

MS: m/z=390 [M+H]⁺.

Reference Example 396

MS: m/z=468 [M+H]⁺

Reference Example 397

MS: m/z=452 [M+H]⁺

Reference Example 398

¹H-NMR (CDCl₃) δ: 1.12-1.32 (6H, m), 4.25 (0.52H, d, J=12.9 Hz), 4.41(0.48H, d, J=13.2 Hz), 4.58-4.79 (2H, m), 4.92-5.03 (2H, m), 5.73(0.48H, d, J=7.8 Hz), 5.89 (0.52H, d, J=7.8 Hz), 6.12 (0.48H, d, J=12Hz), 6.46-6.58 (1.52H, m), 6.74-6.78 (1H, m), 6.98 (1H, t, J=7.5 Hz),7.10-7.14 (1H, m), 7.20-7.50 (4H, m).

Reference Example 399

¹H-NMR (CDCl₃) δ: 1.12-1.31 (6H, m), 4.25 (0.75H. d, J=12.9 Hz), 4.43(0.25H, d, J=12.9 Hz), 4.53-4.60 (0.50H, m), 4.67-4.78 (1.5H, m),4.90-5.05 (2H. m), 5.70 (0.25H, d, J=7.8 Hz, 5.86 (0.75H, d, J=7.5 Hz),6.18 (0.25H, d, J=13.5 Hz), 6.36-6.42 (0.75H, m), 6.49-6.56 (2H, m),6.69-6.80 (1H, m), 6.94 (1H, d, J=7.8 Hz), 7.10-7.19 (0.25H, m),7.21-7.50 (3.75H, m).

Reference Example 400

MS: m/z=452 [M+H]⁺

Reference Example 401

MS: m/z=452 [M+H]⁺

Reference Example 402

MS: m/z=470 [M+H]⁺

Reference Example 403

MS: m/z=436 [M+H]⁺

Reference Example 404

MS: m/z=452 [M+H]⁺

Reference Example 405

MS: m/z=452 [M+H] P

Reference Example 406

MS: m/z=490 [M+H]⁺

Reference Example 407

MS: m/z=436 [M+H]⁺

Reference Example 408

MS: m/z=452 [M+H]⁺

Reference Example 409

MS: m/z=452 [M+H]⁺

Reference Example 410

MS: m/z=490 [M+H]⁺

Reference Example 411

MS: m/z=506 [M+H]⁺

Reference Example 412

¹H-NMR (CDCl₃) δ: 1.13-1.31 (12H, m), 3.28-3.37 (0.50H, m), 3.44-3.53(0.50H, m), 4.29-4.36 (1H, m), 4.65-4.76 (2H, m), 4.98-5.05 (2H, m),6.37 (0.5H, d, J=12.9 Hz), 6.45 (0.5H, d, J=7.5 Hz), 6.67 (0.5H, t,J=7.8 Hz), 6.81 (0.5H, 7.8 Hz), 6.98-7.08 (2H, m), 7.14 (0.5H, d, J=7.8Hz), 7.22-7.45 (2.5H, m).

Reference Example 413, Reference Example 414

First Step

Compound 413A (200 mg, 0.544 mmol) obtained by the same procedure asthat of Reference example 95, and 6,11-dihydrodibenzo[b,e]thiepin-11-ol(124 mg, 0.554 mmol) were dissolved in acetic acid (8 ml), andconcentrated sulfuric acid (2 ml) was added dropwise underwater-cooling. After the mixture was stirred at room temperature for 30minutes, water was added, and the mixture was extracted with ethylacetate. The organic layer was dried with sodium sulfate, and thesolvent was distilled off under reduced pressure to obtain a crudeproduct of 413B.

Second Step

Compound 413B obtained in the first step was dissolved indichloromethane (2 ml), acetic acid anhydride (0.154 ml, 1.63 mmol),triethylamine (0.226 ml, 1.63 mmol) and 4-(dimethylamino)pyridine (cat.)were added, and the mixture was stirred at room temperature for 30minutes. The solvent was distilled off, the resulting crude product waspurified by silica gel column chromatography, and eluted withchloroform-methanol (97:3, v/v), and diastereomers were resolved. Theywere dissolved in methanol (1 ml) and tetrahydrofuran (1 ml),respectively, a 2N aqueous sodium hydroxide solution (0.198 ml, 0.397mmol) was added, and the mixture was stirred at room temperature for 30minutes. The reaction solution was poured into water, and the mixturewas made acidic with hydrochloric acid, and extracted with ethylacetate. The organic layer was dried with sodium sulfate, and thesolvent was distilled off under reduced pressure. To the resultingcompound were added ethyl acetate-diethyl ether, and thefractionation-precipitated residue was filtered to obtain compound 413(22 mg) and compound 414 (20 mg), respectively.

Reference Example 413

¹H-NMR (DMSO-d₆) δ: 1.20 (3H, d, J=7.4 Hz), 3.92 (1H, d, J=13.6 Hz),4.45 (1H, d, J=13.4 Hz), 5.12 (1H, d, J=12.8 Hz), 5.60 (4H, m),6.87-7.60 (9H, m).

MS: m/z=488 [M+H]⁺

Reference Example 414

MS: m/z=488 [M+H]⁺

According to Reference example 413, compounds 414 to 475 weresynthesized using the same procedure.

Reference Example 415

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, d, J=7.3 Hz), 3.88 (1H, d, J=13.3 Hz),4.41 (1H, d, J=13.3 Hz), 5.07 (1H, d, J=13.0 Hz), 5.42-5.52 (1H, m),5.62 (3H, m), 6.82-7.56 (9H, m).

MS: m/z=488 [M+H]⁺

Reference Example 416

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.3 Hz), 3.88 (1H, d, J=13.3 Hz),4.44 (1H, d, J=12.7 Hz), 5.15 (1H, d, J=12.5 Hz), 5.16 (1H, m), 5.29(1H, s), 5.57 (1H, d, J=13.4 Hz), 5.64 (1H, d, J=7.8 Hz), 6.81-7.45 (9H,m).

MS: m/z=488 [M+H]⁺

Reference Example 417

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=7.2 Hz), 4.32 (1H, d, J=13.9 Hz), 4.49(1H, d, J=13.1 Hz), 4.90 (1H, d, J=13.3 Hz), 5.15 (1H, s), 5.47-5.65(2H, m), 5.83 (1H, d, J=8.1 Hz), 6.69 (1H, d, J=6.5 Hz), 6.80-6.87 (1H,m), 7.07-7.24 (5H, m), 7.54 (1H, d, J=7.9 Hz).

MS: m/z=522 [M+H]⁺.

Reference Example 418

¹H-NMR (CDCl₃) δ: 1.48 (3H, d, J=7.1 Hz), 3.63 (1H, d, J=13.2 Hz), 4.49(1H, d, J=12.6 Hz), 5.03 (1H, s), 5.28-5.45 (2H, m), 5.53 (1H, d, J=13.5Hz), 5.73 (1H, d, J=7.7 Hz), 6.50 (1H, dd, J=8.7, 2.6 Hz), 6.79-6.86(1H, m), 6.90 (1H, d, J=9.1 Hz), 7.02 (1H, dd, J=8.8, 5.2 Hz), 7.10 (1H,ddd, J=8.1, 2.5, 1.2 Hz), 7.25 (1H, d, J=7.7 Hz), 7.30 (1H, dd, J=8.5,5.5 Hz).

MS: m/z=524 [M+H]⁺.

Reference Example 419

¹H-NMR (CDCl₃) δ: 1.50 (3H, d, J=7.1 Hz), 4.28 (1H, d, J=13.7 Hz), 4.50(1H, d, J=12.4 Hz), 5.17 (1H, s), 5.26-5.44 (2H, m), 5.60-5.69 (2H, m),6.65 (1H, d, J=7.4 Hz), 6.73-6.80 (1H, m), 7.01-7.21 (5H, m), 7.48 (1H,d, J=8.0 Hz).

MS: m/z=522 [M+H]⁺.

Reference Example 420

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=7.4 Hz), 3.51 (1H, d, J=13.5 Hz), 4.48(1H, d, J=12.6 Hz), 5.12 (1H, s), 5.28-5.44 (2H, m), 5.60-5.70 (2H, m),6.65 (1H, d, J=7.4 Hz), 6.73-6.80 (1H, m), 7.00-7.06 (2H, m), 7.10 (1H,d, J=8.5 Hz), 7.14 (1H, d, J=8.0 Hz), 7.23 (1H, dd, J=8.2, 2.2 Hz), 7.31(1H, d, J=1.9 Hz).

MS: m/z=522 [M+H]⁺.

Reference Example 421

¹H-NMR (CDCl₃) δ: 1.53 (3H, d, J=7.4 Hz), 3.59 (1H, d, J=13.4 Hz), 4.51(1H, d, J=12.6 Hz), 5.12 (1H, s), 5.30-5.48 (2H, m), 5.62-5.70 (2H, m),6.71 (1H, d, J=7.7 Hz), 6.80-6.83 (1H, m), 7.07-7.11 (2H, m), 7.18 (1H,d, J=7.7 Hz), 7.22 (1H, s), 7.28 (1H, d, J=8.4 Hz), 7.39 (1H, d, J=8.1Hz).

MS: m/z=522 [M+H]⁺.

Reference Example 422

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=7.4 Hz), 3.59 (1H, d, J=13.5 Hz), 4.48(1H, d, J=12.4 Hz), 5.12 (1H, s), 5.29-5.39 (2H, m), 5.66 (1H, d, J=13.5Hz), 5.73 (1H, d, J=7.7 Hz), 6.61 (1H, d, J=8.2 Hz), 6.73 (1H, dd,J=8.2, 2.2 Hz), 7.04 (1H, d, J=2.2 Hz), 7.12-7.20 (2H, m), 7.23-7.27(1H, m), 7.31 (1H, d, J=6.3 Hz), 7.36-7.44 (1H, m).

MS: m/z=522 [M+H]⁺.

Reference Example 423

¹H-NMR (CDCl₃) δ: 1.47 (3H, d, J=7.1 Hz), 3.69 (1H, d, J=13.5 Hz), 4.49(1H, d, J=12.6 Hz), 5.21 (1H, s), 5.27 (1H, d, J=12.6 Hz), 5.30-5.40(1H, m), 5.70 (1H, d, J=7.7 Hz), 5.75 (1H, d, J=13.5 Hz), 6.65 (1H, dd,J=7.8, 1.5 Hz), 6.73 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=7.7 Hz),7.15-7.22 (2H, m), 7.25-7.29 (1H, m), 7.32 (1H, d, J=8.0 Hz), 7.37-7.45(1H, m).

MS: m/z=522 [M+H]⁺.

Reference Example 424

MS: m/z=490 [M+H]⁺.

Reference Example 425

MS: m/z=490 [M+H]⁺.

Reference Example 426

MS: m/z=490 [M+H]⁺.

Reference Example 427

¹HNMR (CDCl₃): 1.14 (3H, d, J=6.9 Hz), 3.64 (1H, d, J=13.5 Hz), 4.48(1H, d, J=12.8 Hz), 4.88 (1H, d, J=12.8 Hz), 5.08 (1H, s), 5.51 (1H, m),5.60 (1H, d, J=13.5 Hz), 5.93 (1H, d, J=8.1 Hz), 6.58 (1H, d, J=8.1 Hz),6.95 (1H, dd, J=2.0, 8.1 Hz), 7.18 (2H, m), 7.29 (1H, m), 7.37-7.45 (2H,m).

Reference Example 428

¹HNMR (CDCl₃) δ: 1.41 (3H, d, J=7.5 Hz), 3.61 (1H, d, J=13.4 Hz), 4.55(1H, d, J=12.5 Hz), 5.06 (1H, d, J=12.5 Hz), 5.16 (1H, s), 5.34 (1H, m),5.63 (1H, d, J=13.4 Hz), 5.87 (1H, d, J=8.1 Hz), 6.61 (1H, d, J=8.1 Hz),6.93 (1H, dd, J=1.8, 8.1 Hz), 7.16-7.41 (5H, m).

Reference Example 429

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=7.4 Hz), 3.64 (1H, d, J=13.5 Hz), 4.44(1H, d, J=13.2 Hz), 4.87 (1H, d, J=13.2 Hz), 5.44-5.57 (1H, m), 5.68(1H, d, J=13.2 Hz), 5.83 (1H, d, J=7.7 Hz), 5.94 (1H, s), 6.78-6.91 (2H,m), 7.08-7.18 (3H, m), 7.28-7.38 (3H, m).

MS: m/z=522 [M+H]⁺.

Reference Example 430

MS: m/z=522 [M+H]⁺.

Reference Example 431

MS: m/z=522 [M+H]⁺.

Reference Example 432

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.4 Hz), 3.70 (1H, d, J=13.5 Hz), 4.43(1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 5.21 (1H, s), 5.46-5.60(1H, m), 5.70 (1H, d, J=13.5 Hz), 5.84 (1H, d, J=7.7 Hz), 6.73 (1H, d,J=7.1 Hz), 6.82-6.89 (1H, m), 7.08-7.17 (2H, m), 7.22 (1H, d, J=7.7 Hz),7.35 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=8.0 Hz), 7.67 (1H, s).

MS: m/z=071 [M+H]⁺.

Reference Example 433

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=7.1 Hz), 3.56 (1H, d, J=13.5 Hz), 4.48(1H, d, J=13.2 Hz), 4.90 (1H, d, J=13.2 Hz), 5.09 (1H, s), 5.46-5.60(1H, m), 5.62 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.7 Hz), 6.69 (1H, d,J=7.4 Hz), 6.84 (1H, dt, J=10.0, 3.5 Hz), 7.04-7.14 (3H, m), 7.17 (1H,d, J=7.7 Hz), 7.42 (1H, dd, J=8.0, 1.6 Hz), 7.55 (1H, d, J=1.9 Hz).

MS: m/z=433 [M+H]⁺.

Reference Example 434

¹H-NMR (CDCl₃) δ: 1.44 (3H, d, J=7.3 Hz), 3.54 (1H, d, J=13.4 Hz), 4.54(1H, d, J=12.5 Hz), 5.10 (1H, d, J=12.5 Hz), 5.16 (1H, s), 5.31-5.45(1H, m), 5.65 (1H, d, J=13.3 Hz), 5.73 (1H, d, J=7.8 Hz), 6.71 (1H, d,J=7.8 Hz), 6.77-6.84 (1H, m), 7.03-7.11 (3H, m), 7.22 (1H, d, J=7.6 Hz),7.40 (1H, dd, J=8.2, 2.0 Hz), 7.48 (1H, d, J=2.0 Hz).

MS: m/z=433 [M+H]⁺.

Reference Example 435

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=7.3 Hz), 3.70 (1H, d, J=13.4 Hz), 4.51(1H, d, J=13.1 Hz), 4.90 (1H, d, J=12.8 Hz), 5.19 (1H, s), 5.44-5.58(1H, m), 5.62 (1H, d, J=13.3 Hz), 5.87 (1H, d, J=7.6 Hz), 6.86 (1H, d,J=7.9 Hz), 7.07 (1H, dd, J=8.2, 1.4 Hz), 7.15-7.22 (2H, m), 7.27-7.51(4H, m).

MS: m/z=433 [M+H]⁺.

Reference Example 436

¹H-NMR (CDCl₃) δ: 1.48 (3H, d, J=7.4 Hz), 3.71 (1H, d, J=13.3 Hz), 4.60(1H, d, J=12.6 Hz), 5.21 (1H, d, J=12.6 Hz), 5.29 (1H, s), 5.32-5.46(1H, m), 5.70 (1H, d, J=13.3 Hz), 5.80 (1H, d, J=7.7 Hz), 6.91 (1H, d,J=7.9 Hz), 7.08 (1H, d, J=7.4 Hz), 7.20-7.29 (2H, m), 7.33-7.51 (4H, m).

MS: m/z=433 [M+H]⁺.

Reference Example 437

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.3 Hz), 3.60 (1H, d, J=13.6 Hz), 4.46(1H, d, J=13.1 Hz), 4.90 (1H, d, J=12.8 Hz), 5.15 (1H, s), 5.47-5.59(1H, m), 5.68 (1H, d, J=13.4 Hz), 5.83 (1H, d, J=7.6 Hz), 6.70 (1H, d,J=7.3 Hz), 6.80-6.88 (1H, m), 7.07-7.26 (6H, m).

MS: m/z=433 [M+H]⁺.

Reference Example 438

¹H-NMR (CDCl₃) δ: 1.42 (3H, d, J=7.3 Hz), 3.57 (1H, d, J=13.3 Hz), 4.55(1H, d, J=12.5 Hz), 5.05 (1H, d, J=12.5 Hz), 5.23 (1H, s), 5.32-5.47(1H, m), 5.70 (1H, d, J=13.4 Hz), 5.77 (1H, d, J=7.6 Hz), 6.74 (1H, d,J=7.8 Hz), 6.79-6.87 (1H, m), 7.04-7.26 (6H, m).

MS: m/z=433 [M+H]⁺.

Reference Example 439

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=7.2 Hz), 2.29 (3H, s), 3.76 (1H, d,J=13.3 Hz), 4.54 (1H, d, J=13.1 Hz), 4.92 (1H, d, J=13.1 Hz), 5.18 (1H,s), 5.50-5.62 (1H, m), 5.71 (1H, d, J=13.4 Hz), 5.84 (1H, d, J=7.7 Hz),6.63 (1H, d, J=7.4 Hz), 6.78 (1H, t, J=7.6 Hz), 7.06 (1H, d, J=7.6 Hz),7.17 (1H, d, J=7.7 Hz), 7.23 (1H, d, J=7.6 Hz), 7.28-7.34 (1H, m),7.39-7.51 (2H, m).

MS: m/z=433 [M+H]⁺.

Reference Example 440

¹H-NMR (CDCl₃) δ: 1.45 (3H, d, J=7.2 Hz), 2.27 (3H, s), 3.74 (1H, d,J=13.3 Hz), 4.61 (1H, d, J=12.4 Hz), 5.07 (1H, d, J=12.4 Hz), 5.27 (1H,s), 5.31-5.44 (1H, m), 5.75 (1H, d, J=13.3 Hz), 5.80 (1H, d, J=7.7 Hz),6.67 (1H, d, J=7.1 Hz), 6.77 (1H, t, J=7.6 Hz), 7.04 (1H, d, J=7.1 Hz),7.21-7.47 (5H, m).

MS: m/z=433 [M+H]⁺.

Reference Example 441

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz),4.45 (1H, d, J=13.4 Hz), 5.08 (1H, d, J=12.8 Hz), 5.56 (4H, m),6.84-7.54 (8H, m).

Reference Example 442

¹H-NMR (DMSO-d₆) δ: 1.37 (3H, d, J=7.2 Hz), 3.98 (1H, d, J=13.4 Hz),4.48 (1H, d, J=13.1 Hz), 5.21 (1H, d, J=12.9 Hz), 5.22 (1H, m), 5.38(1H, s), 5.52 (1H, d, J=13.4 Hz), 5.67 (1H, d, J=7.6 Hz), 6.87-7.57 (8H,m).

Reference Example 443

¹H-NMR (DMSO-d₆) δ: 1.19 (3H, d, J=7.2 Hz), 3.92 (1H, d, J=13.4 Hz),4.43 (1H, d, J=13.1 Hz), 5.05 (1H, d, J=13.0 Hz), 5.54 (4H, m), 7.29(8H, m).

MS: m/z=522 [M+H]⁺

Reference Example 444

¹H-NMR (DMSO-d₆) δ: 1.13 (3H, d, J=7.0 Hz), 4.00 (1H, d, J=14.2 Hz),4.40 (1H, d, J=13.3 Hz), 5.05 (1H, d, J=13.3 Hz), 5.44 (1H, m),5.62-5.71 (3H, m), 6.82-7.56 (8H, m).

MS: m/z=506 [M+H]⁺

Reference Example 445

¹H-NMR (DMSO-d₆) δ: 1.23 (3H, d, J=7.2 Hz), 4.14 (1H, d, J=13.8 Hz),4.60 (1H, d, J=13.6 Hz), 5.10 (1H, d, J=13.3 Hz), 5.48 (1H, d, J=15.6Hz) 5.49 (1H, m), 5.69 (1H, d, J=7.9 Hz), 5.70 (1H, s), 6.89-7.47 (8H,m).

MS: m/z=506 [M+H]⁺

Reference Example 446

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, d, J=6.9 Hz), 3.93 (1H, d, J=13.1 Hz),4.49 (1H, d, J=13.4 Hz), 5.05 (1H, d, J=13.7 Hz), 5.57 (4H, m),6.87-7.61 (8H, m).

MS: m/z=522 [M+H]⁺

Reference Example 447

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, d, J=7.2 Hz), 3.98 (1H, d, J=13.3 Hz),4.48 (1H, d, J=12.9 Hz), 5.21 (1H, d, J=14.4 Hz), 5.22 (1H, m), 5.39(1H, s), 5.52 (1H, d, J=13.6 Hz), 5.67 (1H, d, J=7.6 Hz), 6.88-7.57 (8H,m).

MS: m/z=506 [M+H]⁺

Reference Example 448

¹H-NMR (DMSO-d₆) δ: 1.19 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz),4.44 (1H, d, J=13.3 Hz), 5.12 (1H, d, J=13.1 Hz), 5.46-5.68 (3H, m),5.76 (1H, d, J=7.6 Hz), 7.27 (8H, m).

MS: m/z=506 [M+H]⁺

Reference Example 449

¹H-NMR (DMSO-d₆) δ: 1.14 (3H, d, J=7.2 Hz), 3.93 (1H, d, J=13.3 Hz),4.40 (1H, d, J=13.1 Hz), 5.07 (1H, d, J=13.0 Hz), 5.46 (1H, m), 5.62(1H, d, J=15.6 Hz), 5.64 (1H, s), 5.75 (1H, d, J=7.6 Hz), 6.94-7.55 (8H,m).

MS: m/z=522 [M+H]⁺

Reference Example 450

¹H-NMR (DMSO-d₆) δ: 1.14 (3H, d, J=7.2 Hz), 4.03 (1H, d, J=13.3 Hz),4.41 (1H, d, J=13.3 Hz), 5.06 (1H, d, J=13.0 Hz), 5.46 (1H, m), 5.69(3H, m), 6.88-7.57 (8H, m).

MS: m/z=522 [M+H]⁺

Reference Example 451

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.2 Hz), 4.03 (1H, d, J=13.3 Hz),4.43 (1H, d, J=13.0 Hz), 5.14 (1H, t, J=12.6 Hz), 5.15 (1H, m), 5.42(1H, s), 5.63 (1H, d, J=13.5 Hz), 5.65 (1H, d, J=7.8 Hz), 6.88-7.44 (8H,m).

MS: m/z=522 [M+H]⁺

Reference Example 452

¹H-NMR (DMSO-d₆) δ: 1.42 (3H, d, J=7.2 Hz), 4.14 (11H, d, J=13.9 Hz),4.57 (11H, d, J=13.1 Hz), 5.14 (1H, d, J=13.0 Hz), 5.15 (1H, m), 5.30(1H, d, J=13.0 Hz), 5.40 (1H, s), 5.68 (1H, d, J=7.7 Hz), 6.89-7.38 (8H,m).

MS: m/z=506 [M+H]⁺

Reference Example 453

¹H-NMR (DMSO-d₆) δ: 1.40 (3H, d, J=7.4 Hz), 4.05 (1H, d, J=13.4 Hz),4.47 (1H, d, J=13.1 Hz), 5.18 (1H, m), 5.19 (1H, d, J=13.2 Hz), 5.46(1H, s), 5.65 (1H, d, J=13.4 Hz), 5.74 (1H, d, J=7.6 Hz), 6.89-7.52 (8H,m).

MS: m/z=506 [M+H]⁺

Reference Example 454

¹H-NMR (DMSO-d₆) δ: 1.20 (3H, d, J=7.2 Hz), 3.89 (1H, d, J=13.4 Hz),4.46 (1H, d, J=13.4 Hz), 5.05 (1H, d, J=13.4 Hz), 5.44-5.66 (4H, m),6.83-7.63 (8H, m).

MS: m/z=506 [M+H]⁺

Reference Example 455

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, d, J=7.3 Hz), 3.92 (1H, d, J=13.3 Hz),4.39 (1H, d, J=13.1 Hz), 5.07 (1H, d, J=13.3 Hz), 5.47 (1H, m), 5.60(1H, d, J=13.3 Hz), 5.68 (1H, s), 5.72 (1H, d, J=7.6 Hz), 7.07-7.54 (8H,m).

MS: m/z=522 [M+H]⁺

Reference Example 456

¹H-NMR (DMSO-d₆) δ: 1.13 (5H, d, J=6.3 Hz), 4.00 (1H, d, J=13.4 Hz),4.52 (1H, d, J=13.6 Hz), 5.09 (1H, d, J=13.3 Hz), 5.49-5.69 (4H, m),6.84-7.51 (8H, m).

MS: m/z=506 [M+H]⁺

Reference Example 457

¹H-NMR (DMSO-d₆) δ: 1.40 (3H, d, J=7.2 Hz), 4.02 (1H, d, J=13.1 Hz),4.53 (1H, d, J=13.3 Hz), 5.20 (1H, d, J=12.9 Hz), 5.26 (1H, m), 5.67(3H, m), 7.18 (8H, m).

MS: m/z=506 [M+H]⁺

Reference Example 458

¹H-NMR (DMSO-d₆) δ: 1.15 (3H, d, J=7.3 Hz), 3.91 (1H, d, J=13.4 Hz),4.39 (1H, d, J=13.3 Hz), 5.06 (1H, d, J=13.3 Hz), 5.45 (1H, m), 5.62(1H, s), 5.63 (1H, t, J=13.5 Hz), 5.74 (1H, d, J=7.6 Hz), 6.71-7.55 (8H,m).

MS: m/z=506 [M+H]⁺

Reference Example 459

¹H-NMR (DMSO-d₆) δ: 1.39 (3H, d, J=7.4 Hz), 3.95 (1H, d, J=13.4 Hz),4.46 (1H, d, J=12.9 Hz), 5.19 (1H, d, J=13.1 Hz), 5.20 (1H, m), 5.41(1H, s), 5.62 (1H, d, J=13.4 Hz), 5.76 (1H, d, J=7.7 Hz), 6.72-7.50 (8H,m).

MS: m/z=506 [M+H]⁺

Reference Example 460

¹H-NMR (DMSO-d₆) δ: 1.42 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz),4.50 (1H, d, J=13.1 Hz), 5.17 (1H, d, J=12.4 Hz), 5.18 (1H, m), 5.39(1H, s), 5.60-5.69 (2H, m), 6.87-7.42 (8H, m).

MS: m/z=506 [M+H]⁺

Reference Example 461

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.2 Hz), 3.91 (1H, d, J=13.0 Hz),4.43 (1H, d, J=13.1 Hz), 5.15 (1H, d, J=12.8 Hz), 5.16 (1H, m), 5.41(1H, s), 5.47 (1H, d, J=13.0 Hz), 5.69 (1H, d, J=7.6 Hz), 7.00-7.45 (8H,m).

MS: m/z=506 [M+H]⁺

Reference Example 462

¹H-NMR (DMSO-d₆) δ: 1.21 (3H, d, J=7.3 Hz), 3.97 (1H, d, J=13.3 Hz),4.46 (1H, d, J=13.1 Hz), 5.09 (1H, d, J=13.6 Hz), 5.50 (1H, m), 5.51(1H, d, J=12.8 Hz), 5.65 (1H, s), 5.72 (1H, d, J=7.6 Hz), 6.85-7.55 (7H,m).

MS: m/z=524 [M+H]⁺

Reference Example 463

MS: m/z=568 [M+H]⁺

Reference Example 464

MS: m/z=502 [M+H]⁺

Reference Example 465

MS: m/z=502 [M+H]⁺

Reference Example 466

MS: m/z=540 [M+H]⁺

Reference Example 467

MS: m/z=540 [M+H]⁺

Reference Example 468

¹HNMR (CDCl₃) δ: 1.13 (3H, d, J=5.8 Hz), 4.20 (1H, d, J=13.6 Hz), 4.58(1H, d, J=12.7 Hz), 4.99 (1H, d, J=12.7 Hz), 5.29-5.42 (3H, m), 5.84(1H, d, J=7.8 Hz), 6.60 (1H, m), 6.79-7.01 (3H, m), 7.19-7.28 (4H, m).

MS: m/z=524 [M+H]⁺.

Reference Example 469

¹HNMR (CDCl₃) δ: 1.19 (3H, d, J=7.6 Hz), 4.21 (1H, d, J=13.9 Hz), 4.48(1H, d, J=13.3 Hz), 4.89 (1H, d, J=13.3 Hz), 5.22 (1H, s), 5.37 (1H, dd,J=2.1, 13.9 Hz), 5.52 (1H, m), 5.86 (1H, d, J=7.6), 6.55 (1H, m), 6.83(1H, m), 6.96 (1H, m), 7.14 (1H, d, J=7.6 Hz), 7.19-7.30 (4H, m).

MS: m/z=524 [M+H]⁺.

Reference Example 470

¹HNMR (CDCl₃) δ: 1.19 (3H, d, J=7.3 Hz), 3.65 (1H, d, J=13.5 Hz), 4.47(1H, d, J=13.0 Hz), 4.87 (1H, d, J=13.0 Hz), 5.18 (1H, s), 5.50 (1H, m),5.69 (1H, d, J=13.5 Hz), 5.85 (1H, d, J=7.8 Hz), 6.53 (1H, m), 6.83 (1H,m), 6.91-7.01 (2H, m), 7.11 (1H, d, J=7.6 Hz), 7.10-7.20 (3H, m).

MS: m/z=524 [M+H]⁺.

Reference Example 471

¹HNMR (CDCl₃) δ: 1.13 (3H, d, J=6.1 Hz), 3.63 (1H, d, J=13.5 Hz), 4.56(1H, d, J=12.5 Hz), 5.02 (1H, d, J=12.5 Hz), 5.26 (1H, s), 5.38 (1H, m),5.71 (1H, d, J=13.5 Hz), 5.81 (1H, d, J=7.8 Hz), 6.57 (1H, m), 6.81 (1H,m), 6.91 (1H, m), 6.99 (1H, dd, J=2.6, 8.2 Hz), 7.05 (1H, dd, J=2.6, 8.7Hz), 7.17 (2H, m), 7.19 (1H, d, J=7.6 Hz).

MS: m/z=524 [M+H]⁺.

Reference Example 472

¹HNMR (CDCl₃) δ: 1.21 (3H, d, J=7.4 Hz), 3.66 (1H, d, J=13.5 Hz), 4.47(1H, d, J=13.3 Hz), 4.88 (1H, d, J=13.3 Hz), 5.17 (1H, s), 5.52 (1H, m),5.66 (1H, d, J=13.5 Hz), 5.85 (1H, d, J=7.7 Hz), 6.54 (1H, m), 6.83 (1H,m), 6.95 (1H, m), 7.11-7.14 (2H, m), 7.23-7.29 (2H, m), 7.41 (1H, d,J=2.0 Hz).

MS: m/z=540 [M+H]⁺.

Reference Example 473

¹HNMR (CDCl₃) δ: 1.13 (3H, d, J=6.2 Hz), 3.63 (1H, d, J=13.5 Hz), 4.55(1H, d, J=12.6 Hz), 5.04 (1H, d, J=12.6 Hz), 5.25 (1H, s), 5.38 (1H, m),5.69 (1H, d, J=13.5 Hz), 5.80 (1H, d, J=7.7 Hz), 6.58 (1H, m), 6.82 (1H,m), 6.92 (1H, m), 7.13 (1H, m), 7.19 (1H, d, J=7.7 Hz), 7.24-7.29 (2H,m), 7.34 (1H, d, J=2.2 Hz).

MS: m/z=540 [M+H]⁺.

Reference Example 474

¹HNMR (CDCl₃) δ: 1.19 (3H, d, J=7.3 Hz), 4.40 (1H, d, J=13.9 Hz), 4.59(1H, d, J=13.0 Hz), 5.02 (1H, d, J=13.0 Hz), 5.31 (1H, s), 5.39 (1H, m),5.66 (1H, d, J=13.9 Hz), 5.84 (1H, d, J=7.8 Hz), 6.58 (1H, m), 6.82 (1H,m), 6.92 (1H, m), 7.10 (1H, m), 7.19 (1H, dd, J=3.7, 7.9 Hz), 7.20-7.26(2H, m), 7.51 (1H, m).

MS: m/z=540 [M+H]⁺.

Reference Example 475

MS: m/z=522 [M+H]⁺.

Reference Example 476

First Step

Compound 476A (3.00 g, 9.83 mmol) synthesized by the same procedure asthat of Reference example was dissolved in dimethylformamide (30 ml),copper(I) cyanide (2.64 g, 29.5 mmol) was added, and the mixture wasstirred at 150° C. for 7 hours. The reaction solution was cooled to roomtemperature, and filtered with celite. To the filtrate was added water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water. The solvent was distilled off under reduced pressure,and the resulting crude product was purified by silica gel columnchromatography, and eluted with n-hexane-ethyl acetate (1:1, v/v). Tothe resulting compound was added n-hexane, and the precipitated residuewas filtered to obtain 1.81 g of a white solid 476B.

¹H-NMR (CDCl₃) δ: 4.29 (2H, s), 7.28-7.48 (4H, m), 7.78 (2H, t, J=7.5Hz), 8.20 (1H, dd, J=8.1, 1.5 Hz).

Second Step

According to the same procedure as that of Reference example 107,compound 476 was synthesized.

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, d, J=7.0 Hz), 4.01 (1H, d, J=14.0 Hz),4.65 (1H, d, J=13.7 Hz), 5.04 (1H, d, J=13.3 Hz), 5.45 (1H, t, J=8.1Hz), 5.66 (1H, d, J=7.6 Hz), 5.74 (1H, s), 5.84 (1H, d, J=14.0 Hz),6.87-7.93 (7H, m).

MS: m/z=513 [M+H]⁺

Reference Example 477

First Step

To compound 476B (859 mg, 3.42 mmol) was added concentrated sulfuricacid (13 ml), and the mixture was stirred at room temperature for 18hours, and at 60° C. for 2 hours. The reaction solution was added towater, the mixture was extracted with ethyl acetate, and the organiclayer was dried with sodium sulfate. The solvent was concentrated underreduced pressure to obtain 387 mg of a pale yellow solid. To theresulting compound was added methanol (10 ml), a ION aqueous sodiumhydroxide solution (6 ml) was added, and the mixture was stirred at 90°C. for 5 hours. The reaction solution was cooled to room temperature,water was added, and the mixture was washed with dichloromethane. To theaqueous layer was added dilute hydrochloric acid, the mixture wasextracted with ethyl acetate, and the organic layer was dried withsodium sulfate. The solvent was concentrated under reduced pressure toobtain 296 mg of a yellow solid 477A.

Second Step

Compound 477A (179 mg, 0.662 mmol) obtained in the first step wasdissolved in dichloromethane (4 ml), dimethylamine hydrochloride (108mg, 1.32 mmol), EDCI (190 mg, 0.993 mmol),1H-benzo[d][1,2,3]triazol-1-ol (89.0 mg, 0.662 mmol) and triethylamine(0.3 ml) were added, and the mixture was stirred at room temperature for2 hours. To the reaction solution was added water, the mixture wasextracted with ethyl acetate, and the organic layer was washed with anaqueous sodium bicarbonate solution, and dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingcrude product was purified by silica gel column chromatography, andeluted with n-hexane-ethyl acetate (1:1, v/v), to obtain 170 mg of acolorless gummy substance 477B.

¹H-NMR (CDCl3) δ: 2.99 (3H, s), 3.23 (3H, s), 4.08 (2H, s), 7.28-7.44(5H, m), 7.58 (1H, t, J=4.4 Hz), 8.22 (1H, dd, J=8.1, 1.5 Hz).

Third Step

According to the same procedure as that of Reference example 107,compound 477 was synthesized.

MS: m/z=559 [M+H]⁺

Reference Example 478

First Step

Compound 277 (971 mg, 2.11 mmol) was dissolved in dimethylformamide (10ml), cesium carbonate (2.75 g, 8.45 mmol) and benzyl bromide (0.753 ml,6.34 mmol) were added, and the mixture was stirred at room temperaturefor 4 hours. The reaction solution was poured into water, then extractedwith ethyl acetate, and the organic layer was washed with water, anddried with sodium sulfate. The solvent was distilled off under reducedpressure, to the resulting compound were added dichloromethane-diethylether, and the precipitated residue was filtered to obtain 740 mg of awhite solid 478A.

Second Step

Compound 478A (740 mg, 1.35 mmol) was dissolved in tetrahydrofuran (7ml) and methanol (7 ml), a 2N aqueous sodium hydroxide solution (3.37ml, 6.73 mmol) was added, and the mixture was stirred at roomtemperature for 30 minutes. To the reaction solution was added dilutehydrochloric acid to make the solution acidic, the mixture was extractedwith chloroform, and the organic layer was dried with sodium sulfate.The solvent was concentrated under reduced pressure to obtain 618 mg ofa white solid 478B.

MS: m/z=508 [M+H]⁺

Third Step

Compound 478B (505 mg, 0.995 mmol) was dissolved in tetrahydrofuran (10ml), triphenylphosphine (391 mg, 1.49 mmol), phthalimide (220 mg, 1.49mmol) and azodicarboxylic acid diisopropyl ester (0.290 ml, 1.49 mmol)were added, and the mixture was stirred at room temperature for 1 hour.The reaction solution was concentrated under reduced pressure, and theresulting crude product was purified by silica gel columnchromatography, and eluted with chloroform-methanol (97:3, v/v). To theresulting compound were added dichloromethane-diethyl ether, and theprecipitated residue was filtered to obtain 578 mg of a white solid478C.

MS: m/z=637 [M+H]⁺

Fourth Step

To compound 478C (667 mg, 1.05 mmol) was added ethanol (10 ml),hydrazine hydrate (0.254 ml, 5.24 mmol) was added, and the mixture wasstirred at 90° C. for 2 hours. The reaction solution was cooled to roomtemperature, chloroform was added, insolubles were removed byfiltration, and the filtrate was concentrated under reduced pressure.The resulting crude product was purified by amino column chromatography,and eluted with chloroform-methanol (97:3, v/v). To the resultingcompound were added dichloromethane-diethyl ether, and the precipitatedresidue was filtered to obtain 462 mg of a white solid 478D.

MS: m/z=507 [M+H]⁺

Fifth Step

To compound 478D (100 mg, 0.197 mmol) were added formic acid (1.0 ml)and an aqueous formalin solution (1.0 ml), and the mixture was stirredat 80° C. for 1 hour. To the reaction solution was added a 1N aqueoussodium hydroxide solution, the mixture was extracted withdichloromethane, and the organic layer was dried with sodium sulfate.The resulting crude product was purified by amino column chromatography,and eluted with chloroform-methanol (97:3, v/v), to obtain 56 mg of acolorless oily substance. This compound was dissolved in acetic acid(2.0 ml), concentrated sulfuric acid (0.5 ml) was added dropwise, andthe mixture was stirred at room temperature for 30 minutes. The reactionsolution was poured into an aqueous sodium bicarbonate solution, and wasextracted with chloroform, and the organic layer was dried with sodiumsulfate. The solvent was distilled off under reduced pressure, to theresulting crude product were added dichloromethane-ethyl acetate-diethylether, and the precipitated residue was filtered to obtain 12 mg of awhite solid 478.

MS: m/z=445 [M+H]⁺

Reference Example 479

First Step

To a dichloromethane (50 ml) solution of compound 479A (5.25 g, 11.8mmol) synthesized according to Reference example 95, DIPEA (6.20 mL,35.5 mmol) and Boc2O (5.17 g, 23.7 mmol) was added DMAP (434 mg, 3.55mmol), and the mixture was stirred at room temperature for 4 hours.After the reaction solution was concentrated under reduced pressure, theresidue was dissolved in ethyl acetate. The solution was sequentiallywashed with 0.5N aqueous hydrochloric acid solution and an aqueoussaturated sodium chloride solution, and dried with sodium sulfate. Thesolvent was distilled off, and the resulting oil was purified by silicagel chromatography. The materials were eluted firstly with chloroformand, then, with chloroform-methanol (97:3, v/v). Concentration of anobjective fraction afforded 5.22 g of compound 479B as an oil.

MS: m/z=544 [M+H]⁺.

Second Step

To a THF (340 mL) solution of compound 479B (29.7 g, 102 mmol) andacetic acid (29.7 g, 102 mmol) was added TBAF (1M THF solution, 23.6 g,310 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 16 hours. To the reaction solution were added ethylacetate and water, and the ethyl acetate layer was separated, washedwith water, and dried with sodium sulfate. The solvent was distilledoff, and the resulting oil was solidified by addingdichloromethane-ether, to obtain 2.76 g of compound 479C.

MS: m/z=430 [M+H]⁺.

Third Step

To an ethyl acetate (20 mL) suspension of compound 479C (500 mg, 1.16mmol) was added IBX (652 mg, 2.33 mmol), and the mixture was heated tostir for 3 hours. After the reaction solution was diluted with ethylacetate, insolubles were filtered, and the resulting filtrate wassequentially washed with a 1N aqueous sodium hydroxide solution andwater, and dried with sodium sulfate. After the solvent was distilledoff, and the resulting oil was dissolved in THF (5 mL), dimethylamine(2M THF solution, 0.873 mL, 1.75 mmol) and NaBH(OAc)3 (370 mg, 1.75mmol) were added under ice-cooling, and the mixture was stirred at roomtemperature for 1.5 hours. After 2N aqueous hydrochloric acid solutionwas added to the reaction solution under ice-cooling, the mixture wasmade basic with an aqueous sodium bicarbonate solution. This wasextracted with chloroform, and dried with sodium sulfate. The solventwas distilled off, and the resulting oil was purified by silica gelchromatography. The materials were eluted firstly with chloroform and,then, with chloroform-methanol (93:7, v/v). Concentration of anobjective fraction afforded 437 mg of compound 479D as an amorphoussubstance.

MS: m/z=457 [M+H]⁺.

Fourth Step

Compound 479D (430 mg, 0.942 mmol) was dissolved in acetic acid (10 mL),and the solution was heated to stir for 1 hour. The solvent wasdistilled off, and the resulting oil was purified by silica gelchromatography. The materials were eluted firstly with chloroform and,then, with chloroform-methanol (95:5, v/v). Concentration of anobjective fraction afforded 330 mg of compound 479E as an oil.

MS: m/z=357 [M+H]⁺.

Fifth Step

To an acetic acid (2 mL) solution of compound 479E (50 mg, 0.140 mmol)and dibenzosuberol (29.5 mg, 0.140 mmol) was added dropwise sulfuricacid (0.5 mL), and the mixture was stirred for 30 minutes. To thereaction solution were added ethyl acetate and water, thereafter, theaqueous layer was separated, and neutralized with an aqueous sodiumbicarbonate solution. Extraction was performed using the ethyl acetatelayer, and the extract was washed with water, and dried with sodiumsulfate. The solvent was distilled off, and the resulting oil wassolidified by adding ether, to obtain 17.0 mg of compound 479.

MS: m/z=354 [M+H]⁺.

According to Reference example 478 or Reference example 479, compoundswere synthesized as compounds of Reference examples 480 to 490 using thesame procedure.

Reference Example 480

MS: m/z=477 [M+H]⁺.

Reference Example 481

MS: m/z=512 [M+H]⁺.

Reference Example 482

MS: m/z=501 [M+H]⁺.

Reference Example 483

MS: m/z=519 [M+H]⁺.

Reference Example 484

MS: m/z=514 [M+H]⁺.

Reference Example 485

MS: m/z=532 [M+H]⁺

Reference Example 486

MS: m/z=499 [M+H]⁺.

Reference Example 487

MS: m/z=517 [M+H]⁺.

Reference Example 488

MS: m/z=517 [M+H]⁺.

Reference Example 489

MS: m/z=535 [M+H]⁺.

Reference Example 490

MS: m/z=473 [M+H]⁺

Reference Example 491

According to Reference example 65 and Reference example 107, compound491 was synthesized by the same procedure.

¹H-NMR (DMSO-d₆) δ: 1.10 (3H, d, J=4.0 Hz), 1.12 (3H, d, J=4.6 Hz),2.82-3.06 (2H, m), 3.56 (1H, d, J=17.8 Hz), 4.26 (1H, d, J=13.2 Hz),4.31 (1H, m), 4.51-4.60 (1H, m), 4.97 (1H, d, J=13.1 Hz), 5.39 (1H, s),6.74-7.52 (8H, m).

MS: m/z=460 [M+H]⁺

Reference Example 492

According to Reference example 65 and Reference example 107, compound492 was synthesized by the same procedure.

MS: m/z=478 [M+H]⁺

Reference Example 493

First Step

A dichloromethane (5 mL) solution of compound 493A (258 mg, 1.30 mmol)was cooled to −50° C., and a toluene solution (1M, 1.96 mL) of DIBAL-Hwas added dropwise over 5 minutes while the same temperature wasretained. After the reaction solution was stirred at the sametemperature for 1 hour, temperature was raised to room temperature, andthe mixture was stirred for 2.5 hours. To the reaction solution wasadded an aqueous saturated ammonium chloride solution, thereafter, themixture was stirred at room temperature for 1 hour, and insolubles wereremoved by filtration. The dichloromethane layer was separated, and theaqueous layer was extracted with dichloromethane once. The combinedextracts were washed with water three times, washed with an aqueoussaturated sodium chloride solution, and dried. The solvent was distilledoff, and the resulting oil was subjected to silica gel columnchromatography, and eluted with n-hexane-ethyl acetate. Concentration ofan objective fraction afforded 148 mg of compound 493B as an oil.

¹HNMR (CDCl₃) δ: 1.03-1.44 (5H, m), 1.63-1.83 (5H, m), 2.05-2.13 (1H,m), 3.25 (1H, dd, J=9.5 Hz, 3.4 Hz), 7.16-7.19 (2H, ms), 7.27-7.38 (3H,m), 9.69 (1H, d, J=3.5 Hz).

Second Step

According to Reference example 177, compound 493 was synthesized by thesame procedure.

MS: m/z=410 [M+H]⁺

Using aldehydes which are commercially available or known in thereferences and hydrazines which are commercially available or known inthe references, and according to Reference example 493, compounds 494 to505 were synthesized.

Reference Example 494

MS: m/z=428 [M+H]⁺

Reference Example 495

MS: m/z=420 [M+H]⁺.

Reference Example 496

MS: m/z=376 [M+H]⁺.

Reference Example 497

MS: m/z=500 [M+H]⁺.

Reference Example 498

MS: m/z=404 [M+H]⁺.

Reference Example 499

MS: m/z=382 [M+H]⁺.

Reference Example 500

MS: m/z=382 [M+H]⁺.

Reference Example 501

MS: m/z=368 [M+H]⁺.

Reference Example 502

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.2 Hz), 1.26 (3H, t, J=7.3 Hz),2.87-2.94 (2H, m), 3.10-3.22 (1H, m), 3.79-3.89 (1H, m), 3.98 (1H, d,J=16.9 Hz), 4.17 (1H, d, J=16.8 Hz), 4.28 (1H, d, J=9.8 Hz), 6.04 (1H,d, J=7.2 Hz), 6.54 (2H, t, J=8.1 Hz), 6.73 (1H, d, J=9.8 Hz), 6.95-7.33(6H, m), 7.66 (1H, dd, J=5.3, 3.6 Hz).

MS: m/z=448 [M+H]⁺.

Reference Example 503

MS: m/z=374 [M+H]⁺.

Reference Example 504

MS: m/z=374 [M+H]⁺.

Reference Example 505

MS: m/z=342 [M+H]⁺.

Reference Example 506

According to Reference example 177, using compound 65B, compound 506 wassynthesized by the same procedure.

MS: m/z=470 [M+H]⁺.

Reference Example 507

According to Reference example 65, using compound 506, compound 507 wassynthesized by the same procedure.

MS: m/z=446 [M+H]⁺.

Reference Example 508

First Step

Compound 508A (261 mg, 0.475 mmol) which is a synthetic intermediate ofReference example 491 was dissolved in dimethyformamide (3 ml),triethylamine (0.132 ml, 0.950 mmol) and ethyl chloroformate (0.0910 ml,0.950 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 20 minutes. An aqueous solution (0.5 ml) of sodiumborohydride (71.9 mg, 1.90 mmol) was added at 0° C., and the mixture wasstirred for 30 minutes. The reaction solution was poured into water, themixture was extracted with ethyl acetate, and the organic layer wasdried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting crude product was purified by silica gelcolumn chromatography, and eluted with chloroform-methanol (97:3, v/v).Diethyl ether was added, and the precipitated residue was filtered toobtain 107 mg of a white solid 508B.

MS: m/z=536 [M+H]⁺

Second Step

Compound 508B (100 mg, 0.187 mmol) obtained in the first step wasdissolved in dichloromethane (1 ml), DAST (33.1 mg, 0.205 mmol) wasadded at 0° C., and the mixture was stirred for 30 minutes. The reactionsolution was poured into water, the mixture was extracted withchloroform, and the organic layer was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingcrude product was purified by silica gel column chromatography, andeluted with chloroform-methanol (97:3, v/v), to obtain 28 mg of a paleyellow gummy substance 508C.

MS: m/z=538 [M+H]⁺

Third Step

To compound 508C obtained in the second step were added acetic acid (2ml) and concentrated sulfuric acid (0.5 ml), and the mixture was stirredat room temperature for 20 minutes. The reaction solution was pouredinto water, the mixture was extracted with ethyl acetate, and theorganic layer was dried with sodium sulfate. Diethyl ether was added,and the precipitated residue was filtered to obtain 4.5 mg of a whitesolid 508.

MS: m/z=448 [M+H]⁺

Reference Example 509

According to Reference example 508, compound 509 was synthesized by thesame procedure.

MS: m/z=466 [M+H]⁺

Reference Example 510

First Step

Compound 510A (36.8 g, 259 mmol) was dissolved in dimethylformamide (380ml), potassium carbonate (39.3 g, 285 mmol) and benzyl bromide (30.7 ml,259 mmol) were added, and the mixture was stirred at 80° C. for 8 hours.The reaction was cooled to room temperature, insolubles were removed byfiltration, and the solvent was distilled off under reduced pressure.Water was added, and the precipitated residue was filtered, and driedunder reduced pressure to obtain 46.21 g of a pale brown solid 510B.

Second Step

To compound 510B (4.79 g, 20.6 mmol) obtained in the first step wasadded dichloromethane (70 ml), triethylamine (4.29 ml, 30.9 mmol) andmethanesulfonyl chloride (1.93 ml, 24.8 mmol) were added at 0° C., andthe mixture was stirred for 30 minutes. The reaction solution was pouredinto an aqueous saturated sodium chloride solution, the mixture wasextracted with dichloromethane, the extract was dried with sodiumsulfate, and the solvent was distilled off under reduced pressure. Tothe resulting compound were added n-hexane-dichloromethane, and theprecipitated residue was filtered to obtain 6.56 g of a white solid.This compound was dissolved in acetonitrile (40 ml), tetrabutylammoniumfluoride (75% aqueous solution, 21.6 g, 61.9 mmol) was added, and themixture was stirred at room temperature for 18 hours. The solvent wasdistilled off under reduced pressure, ethyl acetate was added, and themixture was washed with an aqueous sodium bicarbonate solution. Theorganic layer was dried with sodium sulfate, and distilled off underreduced pressure, and the resulting crude product was purified by silicagel column chromatography, and eluted with n-hexane-ethyl acetate (1:1,v/v), to obtain 2.51 g of a white solid 510C.

¹H-NMR (DMSO-d₆) δ: 4.96 (3H, s), 5.30 (3H, d, J=46.4 Hz), 6.56 (1H, d,J=1.8 Hz), 7.39 (5H, m), 8.30 (1H, s).

Third Step

Compound 510C (2.40 g, 10.3 mmol) obtained in the second step wasdissolved in dichloromethane (40 ml), boron tribromide (1Mdichloromethane solution, 10.3 ml, 10.3 mmol) was added dropwise at 0°C., and the mixture was stirred for 30 minutes. Methanol was added, thesolvent was distilled off under reduced pressure, ethyl acetate wasadded, and the mixture was washed with an aqueous saturated sodiumchloride solution. The organic layer was dried with sodium sulfate, thesolvent was distilled off under reduced pressure, and the resultingsolid was washed with diethyl ether to obtain 940 mg of 510D.

¹H-NMR (CDCl₃) δ: 5.20 (2H, d, J=46.3 Hz), 6.40 (1H, s), 6.62 (1H, s),7.91 (1H, s).

Fourth Step

Compound 510D (940 mg, 6.52 mmol) obtained in the third step wasdissolved in methanol (8 ml), a 2N aqueous sodium hydroxide solution(3.26 ml, 6.52 mmol) and a 37% aqueous formaldehyde solution (1.46 ml,19.6 mmol) were added at 0° C., and the mixture was stirred at roomtemperature for 20 hours. To the reaction solution was added an aqueoussaturated ammonium chloride solution, and the solvent was distilled offunder reduced pressure. Hydrochloric acid was added, the mixture wasextracted with chloroform, and the organic layer was dried with sodiumsulfate. The solvent was distilled off under reduced pressure, to theresulting compound were added n-hexane-dichloromethane-ethyl acetate,and the precipitated residue was filtered to obtain 858 mg of a paleyellow solid 510E.

¹H-NMR (CDCl₃) δ: 4.73 (2H, s), 5.19 (2H, d, J=46.1 Hz), 6.55 (1H, s).

Fifth Step

Compound 510E (855 mg, 4.91 mmol) obtained in the fourth step wasdissolved in dimethylformamide (10 ml), potassium carbonate (746 mg,5.40 mmol) and benzyl bromide (0.583 ml, 4.91 mmol) were added, and themixture was stirred at 80° C. for 5 hours. Insolubles were removed byfiltration, and the filtrate was distilled off under reduced pressure.The resulting crude product was purified by silica gel columnchromatography, and eluted with chloroform-methanol (97:3, v/v), toobtain 887 mg of a pale orange solid 510F.

¹H-NMR (CDCl₃) δ: 1.39 (1H, t, J=7.1 Hz), 4.31 (2H, d, J=7.2 Hz), 5.12(2H, dd, J=46.3, 0.7 Hz), 5.23 (2H, s), 6.50 (1H, s), 7.33-7.43 (5H, m).

Sixth Step

Compound 510F (887 mg, 3.36 mmol) obtained in the fifth step wasdissolved in chloroform, manganese dioxide (2.00 g, 23.0 mmol) wasadded, and the mixture was stirred at 80° C. for 2 hours. After cooledto room temperature, the mixture was filtered with celite, and thesolvent was distilled off under reduced pressure to obtain 812 mg of awhite solid 510G.

¹H-NMR (CDCl₃) δ: 5.18 (2H, dd, J=45.8, 0.8 Hz), 5.52 (2H, s), 6.60 (1H,d, J=0.8 Hz), 7.32-7.38 (5H, m), 9.86 (1H, s).

Seventh Step

To compound 510G (884 mg, 3.37 mmol) obtained in the sixth step wereadded acetonitrile and water, monosodium dihydrogen phosphate (809 mg,6.74 mmol) and sodium hypochlorite (1.01 g, 11.1 mmol) were added, andthe mixture was stirred at room temperature for 1 hour. The reactionsolution was concentrated, pH was adjusted to 3 with hydrochloric acid,the mixture was extracted with chloroform, and the extract was driedwith sodium sulfate. The solvent was distilled off under reducedpressure to obtain 404 mg of a white solid 510H.

¹H-NMR (DMSO-d₆) δ: 5.17 (2H, s), 5.38 (2H, d, J=46.2 Hz), 6.73 (1H, d,J=1.5 Hz), 7.34-7.51 (5H, m).

Eighth Step

Compound 510H (402 mg, 1.45 mmol) obtained in the seventh step wasdissolved in dimethylformamide,N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (554 mg, 2.89 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol(195 mg, 1.45 mmol) were added, and the mixture was stirred at roomtemperature for 5 minutes. After propan-2-amine (0.149 ml, 1.73 mmol)was added, the mixture was stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure, water wasadded, the mixture was extracted with ethyl acetate, and the organiclayer was washed with an aqueous sodium bicarbonate solution, and driedwith sodium sulfate. The reaction solution was distilled off underreduced pressure, to the resulting compound was added n-hexane, and theprecipitated residue was filtered to obtain 3.56 g of a white solid5101.

¹H-NMR (CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 4.05 (1H, m), 5.24 (2H, dd,J=45.9, 0.9 Hz), 5.41 (2H, s), 6.59 (1H, q, J=0.9 Hz), 7.40 (5H, m),7.56 (1H, brs).

Ninth Step

Compound 510I (392 mg, 1.23 mmol) obtained in the eighth step wasdissolved in ethanol (6 ml), aqueous ammonia (4 ml) was added, and themixture was stirred at room temperature for 15 hours. The reactionsolution was concentrated under reduced pressure, and the resultingcrude product was purified by silica gel column chromatography, andeluted with chloroform-methanol (97:3, v/v), to obtain 333 mg of a whitesolid 510J.

MS: m/z=319 [M+H]⁺

Tenth Step

Compound 510 was synthesized by the same procedure as that of Referenceexample 95.

MS: m/z=422 [M+H]⁺

Reference Example 511

First Step

A dichloromethane (90 mL) solution of compound 511A (200 mg, 0.664 mmol)and 1,1,3-trimethoxypropane (178.2 mg, 1.33 mmol) was cooled to 1 to 3C,and a boron trifluoride diethyl ether complex (113 mg, 0.797 mmol) wasadded dropwise while the same temperature was retained. After thereaction solution was stirred at the same temperature for 30 minutes,saturated sodium bicarbonate water was added. The dichloromethane layerwas separated, and the aqueous layer was extracted with dichloromethanethree times. After the combined extracts were dried with sodium sulfate,the solvent was distilled off, and the resulting oil was purified bysilica gel column chromatography. The materials were eluted firstly withethyl acetate and, then, with ethyl acetate-methanol (3:2, v/v).Concentration of an objective fraction afforded 179.2 mg of compound511B as an oil.

¹H-NMR (CDCl₃) δ: 1.14 (6H, d, J=6.3 Hz), 2.71 (2H, dd, J=6.0 Hz), 3.34(3H, s), 3.64 (2H, t, J=6.0 Hz), 4.06-4.17 (1H, m), 5.23 (2H, s), 6.34(1H, brs), 6.37 (1H, d, J=7.8 Hz), 7.26-7.43 (6H, m), 7.90 (1H, t, J=5.4Hz).

Second Step

A dimethylformamide (3 ml) solution of compound 511B (179.2 mg, 0.482mmol) was cooled to 1 to 3C, cesium carbonate (786 mg, 2.41 mmol) wasadded while the same temperature was retained, and the mixture wasstirred at the same temperature for 15 minutes. The reaction solutionwas diluted with water, and extracted with chloroform three times. Afterthe combined extracts were dried with sodium sulfate, the solvent wasdistilled off to obtain 130 mg of compound 511C as a solid.

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=6.9 Hz), 1.28 (3H, d, J=6.9 Hz), 1.59(2H, brs), 3.22-3.41 (2H, m), 3.12 (3H, s), 4.57-4.70 (2H, m), 5.19 (1H,d, J=10.5 Hz), 5.38 (1H, brs), 5.54 (1H, d, J=10.5 Hz), 6.34 (1H, d,J=7.8 Hz), 7.26-7.32 (4H, m), 7.49-7.52 (2H, m).

Third Step

To an acetic acid (2 ml) solution of compound 511C (130 mg, 0.350 mmol)and dibenzosuberol (368 mg, 1.75 mmol) was added dropwise sulfuric acid(0.4 ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and the mixture was extracted with ethyl acetate three times. Theextract was washed with water once, and dried with sodium sulfate,thereafter, the solvent was distilled off, and the resulting solid waswashed with diisopropyl ether to obtain 65 mg of compound 511 as asolid.

¹H-NMR (CDCl₃) δ: 1.27 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.6 Hz),1.64-1.74 (1H, m), 1.88-1.99 (1H, m), 2.83 (1H, d, J=4.5 Hz, 4.5 Hz, 9.3Hz), 3.06 (1H, ddd, J=5.6 Hz, 13.2 Hz, 13.2 Hz), 3.19 (3H, s), 3.30-3.44(1H, m), 3.50-3.57 (1H, m), 3.78-3.92 (1H, m), 4.28 (1H, ddd, J=4.2 Hz,13.5 Hz, 13.5 Hz), 4.53 (1H, dd, J=3.3 Hz, 10.8 Hz), 4.96 (1H, s), 5.73(1H, d, J=7.5 Hz), 6.61 (1H, d, J=7.5 Hz), 6.65 (1H, d, J=7.5 Hz),6.89-6.93 (1H, m), 7.08-7.36 (6H, m).

Using amines which are commercially available or known in the referencesand acetals which are commercially available or known in the references,and according to Reference example 511, compounds 512 to 515 weresynthesized.

Reference Example 512

MS: m/z=528 [M+H]⁺

Reference Example 513

MS: m/z=528 [M+H]⁺

Reference Example 514

¹H-NMR (CDCl₃) δ: 1.27 (1H, 3H, d, J=6.9 Hz), 1.48 (3H, d, J=6.6 Hz),1.95 (3H, s), 2.63-2.68 (2H, m), 2.84 (1H, ddd, J=4.8 Hz, 9.3 Hz, 9.3Hz), 3.05 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz), 3.60 (1H, ddd, J=4.8Hz, 4.8 Hz, 17.4 Hz), 3.87-3.98 (1H, m), 4.42 (1H, dd, J=6.6 Hz, 8.1Hz), 4.59 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.93 (1H, s), 5.77 (1H,d, J=7.8 Hz), 6.64 (1H, d, J=6.9 Hz), 6.69 (1H, d, J=7.8 Hz), 6.91 (1H,t, J=6.0 Hz), 7.09-7.38 (6H, m).

Reference Example 515

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=6.9 Hz), 1.44 (3H, d, J=6.9 Hz), 2.80(1H, ddd, J=4.5 Hz, 4.5 Hz, 9.3 Hz), 3.07 (1H, ddd, J=4.5 Hz, 13.5 Hz,13.5 Hz), 3.25 (3H, s), 3.22-3.43 (2H, m), 3.55 (1H, ddd, J=4.2 Hz, 4.2Hz, 8.7 Hz), 3.85-3.94 (1H, m), 4.36 (1H, dd, J=5.1 Hz, 14.1 Hz),4.42-4.48 (1H, m), 4.92 (1H, s), 5.78 (1H, d, J=7.5 Hz), 6.59 (1H, d,J=7.8 Hz), 6.64 (1H, d, J=7.5 Hz), 6.91 (1H, t, J=6.9 Hz), 7.09-7.36(6H, m).

Reference Example 516

First Step

To a toluene (3 ml) solution of compound 516A (100 mg, 0.332 mmol) and3-(methylthio)propanal (52 mg, 0.498 mmol) was added acetic acid (30 mg,0.500 mmol), and the mixture was refluxed for 30 minutes. After cooledto room temperature, the solvent was distilled off, and the resultingcrude product was dissolved in dimethylformamide (3 ml). The solutionwas cooled to 1 to 3° C., cesium carbonate (541 mg, 1.66 mmol) was addedwhile the same temperature was retained, and the mixture was stirred atthe same temperature for 30 minutes. The reaction solution was dilutedwith water, and the mixture was extracted with ethyl acetate threetimes. The combined extracts were washed with water three times, anddried with sodium sulfate, and the solvent was distilled off. Theresulting oil was purified by silica gel column chromatography. Thematerials were eluted firstly with ethyl acetate and, then, with ethylacetate-methanol (7:3, v/v). Concentration of an objective fractionafforded 84.7 mg of compound 516B as an oil.

¹H-NMR (CDCl₃) δ: 1.21 (3H, J=6.9 Hz), 1.28 (3H, d, J=6.9 Hz), 1.31-1.56(2H, m), 2.05 (3H, s), 2.46 (2H, dd, J=5.4 Hz, 7.8 Hz), 4.57-4.71 (2H,m), 5.18 (1H, d, J=10.5 Hz), 5.51 (1H, d, J=10.5 Hz), 5.66 (1H, brs),6.33 (1H, d, J=7.8 Hz), 7.19-7.35 (4H, m), 7.46-7.49 (2H, m).

Second Step

Compound 516 was synthesized by the same procedure as that of Referenceexample 511.

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.6 Hz),1.82-1.89 (2H, m), 1.99 (3H, s), 2.41-2.58 (2H, m), 2.86 (1H, ddd, J=4.5Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H, m), 3.53 (1H, ddd, J=4.5 Hz, 4.5Hz, 17.7 Hz), 4.87-3.96 (1H, m), 4.21 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9Hz), 4.53 (1H, dd, J=5.1 Hz, 8.7 Hz), 4.96 (1H, s), 5.74 (1H, d, J=7.5Hz), 6.62 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=9.0 Hz), 6.89-6.94 (1H, m),7.07-7.37 (6H, m).

Using amines which are commercially available or known in the referencesand aldehydes which are commercially available or known in thereferences, and according to Reference example 516, compounds 517 to 526were synthesized.

Reference Example 517

MS: m/z=500 [M+H]⁺

Reference Example 518

¹H-NMR (CDCl₃) δ: 1.78 (3H, t, J=6.9 Hz), 1.19-1.30 (1H, m), 1.29 (3H,d, J=6.9 Hz), 1.43-1.62 (3H, m), 1.50 (3H, d, J=6.9 Hz), 2.84 (1H, ddd,J=4.5 Hz, 4.5 Hz, 14.1 Hz), 3.00-3.11 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9Hz), 3.52 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.4 Hz), 3.79-3.88 (1H, m),4.23-4.35 (2H, m), 4.96 (1H, s), 5.74 (1H, d, J=7.8 Hz), 6.61 (1H, d,J=7.5 Hz), 6.65 (1H, dd, J=1.2 Hz, 7.8 Hz), 6.91 (1H, ddd, J=1.5 Hz, 7.5Hz, 7.5 Hz), 7.08-7.37 (6H, m).

Reference Example 519

¹H-NMR (CDCl₃) δ: 1.44 (3H, d, J=6.9 Hz), 1.54 (3H, d, J=6.6 Hz), 1.88(1H, ddd, J=3.9 Hz, 3.9 Hz, 14.4 Hz), 2.72 (1H, ddd, J=3.6 Hz, 14.1 Hz,14.1 Hz), 3.15 (1H, ddd, J=4.2 Hz, 4.2 Hz, 16.5 Hz), 3.54 (1H, dd, J=3.0Hz, 14.4 Hz), 3.66 (1H, ddd, J=3.9 Hz, 13.8 Hz, 13.8 Hz), 4.03 (1H, dd,J=10.5 Hz, 14.1 Hz), 4.27-4.26 (1H, m), 4.64 (1H, dd, J=2.7 Hz, 10.5Hz), 4.92 (1H, s), 5.80 (1H, d, J=7.8 Hz), 6.62-6.70 (2H, m), 6.69 (1H,d, J=7.8 Hz), 6.89 (1H, t, J=7.5 Hz), 6.96 (1H, d, J=7.5 Hz), 7.09-7.25(4H, m), 7.77-7.89 (4H, m).

Reference Example 520

¹H-NMR (CDCl₃) δ: 1.30 (3H, d, J=6.6 Hz), 1.54 (3H, d, J=6.6 Hz), 2.83(1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 3.03-3.14 (1H, m), 3.21 (3H, s),3.30 (3H, s), 3.53 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 3.61-3.70 (1H,m), 4.18 (1H, d, J=5.4 Hz), 4.26 (1H, d, J=5.4 Hz), 4.45 (1H, ddd, J=4.5Hz, 13.8 Hz, 13.8 Hz), 4.92 (1H, s), 5.72 (1H, d, J=7.8 Hz), 6.63 (1H,d, J=7.8 Hz), 6.65 (1H, d, J=6.6 Hz), 6.91 (1H, t, J=6.0 Hz), 7.08-7.36(6H, m).

Reference Example 521

¹H-NMR (CDCl₃) δ: 1.30 (2.52H, d, J=6.9 Hz), 1.36 (0.48H, d, J=6.9 Hz),1.42 (0.48H, d, J=6.9 Hz), 1.50 (2.52H, d, J=6.9 Hz), 1.74-1.98 (1H, m),2.00-2.12 (1H, m), 2.16-2.35 (1H, m), 2.89 (1H, ddd, J=5.1 Hz, 5.1 Hz,13.5 Hz), 3.06 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9H), 3.52 (1H, d, J=4.2Hz, 4.2 Hz, 17.4 Hz), 3.86-3.96 (1H, m), 4.15 (1H, ddd, J=3.9 Hz, 13.5Hz, 13.5 Hz), 4.32 (1H, dd, J=3.9 Hz, 10.8 Hz), 4.48-4.64 (1H, m), 4.97(0.84H, s), 5.30 (0.16H, s), 5.73 (0.84H, d, J=7.8 Hz), 6.20 (0.16H, d,J=7.5 Hz), 6.45 (0.16H, brs), 6.61 (1H, d, J=7.5 Hz), 6.64 (0.84H, d,J=8.7 Hz), 6.92 (1H, t, J=6.3 Hz), 7.10 (1H, d, J=7.5 Hz), 7.15-7.39(3H, m).

Reference Example 522

¹H-NMR (CDCl₃) δ: 1.28 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.9 Hz),1.54-1.79 (4H, m), 2.84 (1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 3.05 (1H,ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 3.17 (3H, s), 3.17-3.21 (2H, m), 3.52(1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.83-3.92 (1H, m), 4.22-4.32 (2H,m), 4.96 (1H, s), 5.73 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=7.8 Hz), 6.65(1H, d, J=8.1 Hz), 6.92 (1H, t, J=7.2 Hz), 7.07-7.37 (6H, m).

Reference Example 523

¹H-NMR (CDCl₃) δ: 1.19-1.28 (1H, m), 1.28 (3H, d, J=6.9 Hz), 1.40-1.82(4H, m), 1.48 (3H, d, J=6.6 Hz), 2.89-3.00 z81H, m), 3.17 (3H, s),3.20-3.27 (2H, m), 3.31-3.40 (1H, m), 3.44-3.53 (1H, m), 3.86-3.98 (2H,m), 4.38 (1H, dd, J=3.6 Hz, 10.5 Hz), 5.05 (1H, s), 5.84 (1H, d, 7.5Hz), 6.48-6.50 (1H, m), 6.66-6.69 (1H, m), 6.89-7.00 (2H, m), 7.05 (1H,d, 7.2 Hz), 7.11-7.24 (2H, m).

Reference Example 524

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.9 Hz), 1.42-1.83 (4H, m), 1.48 (3H,d, J=6.6 Hz), 2.80 (11H, ddd, J=4.5 Hz, 4.5 Hz), 14.4H), 2.94-3.11 (11H,m), 3.18 (3H, s), 3.21-3.26 (2H, m), 3.49 (1H, ddd, J=4.2 Hz, 4.2 Hz,18.0 Hz), 3.82-3.91 (1H, m), 4.20-4.33 (2H, m), 5.83 (1H, s), 5.84 (1H,d, J=7.8 Hz), 6.58-6.72 (2H, m), 6.91-6.94 (1H, m), 7.11-7.30 (4H, m).

Reference Example 525

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.9 Hz), 1.47 (3H, d, J=6.6 Hz), 2.10(3H, s), 2.78 (1H, ddd, J=4.2 Hz, 4.2 Hz, 13.8 Hz), 2.97 (3H, s),3.01-3.13 (2H, m), 3.47 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.65 (1H,dd, J=3.3 Hz, 14.1 Hz), 3.99-4.23 (2H, m), 4.70 (1H, dd, J=3.3 Hz, 10.2Hz), 4.95 (1H, s), 5.78 (1H, d, J=7.8 Hz), 6.61 (1H, d, J=7.8 Hz), 6.65(1H, d, J=7.5 Hz), 6.93 (1H, t, J=6.6 Hz), 7.09 (1H, d, J=7.5 Hz),7.15-7.27 (4H, m), 7.30-7.37 (1H, m).

Reference Example 526

¹H-NMR (CDCl₃) δ: 1.57-1.34 (1H, m), 1.29 (3H, d, J=6.9 Hz), 1.41-1.52(1H, m), 1.48 (3H, d, J=6.6 Hz), 1.59-1.81 (2H, m), 2.80 (1H, ddd, 4.5Hz, 4.5 Hz, 14.4 Hz), 3.04 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz),3.14-3.26 (2H, m), 3.18 (3H, s), 3.49 (1H, ddd, J=4.8 Hz, 4.8 Hz, 17.7Hz), 3.84-3.93 (1H, m), 4.23-4.34 (2H, m), 4.96 (1H, s), 5.81 (1H, d,J=7.5 Hz), 6.60-6.79 (3H, m), 6.81 (1H, d, J=9.3 Hz), 6.92 (1H, ddd,J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.19-7.24 (1H, m).

Reference Example 527

First Step

A DMF (0.2 mL) solution of compound 527A (36 mg, 0.09 mmol) synthesizedaccording to the method of synthesizing compound 516 was cooled to 1 to3° C., 5-chlorodibenzosuberane (97 mg, 0.43 mmol) and cesium carbonate(138 mg, 0.43 mmol) were added, and the mixture was stirred at roomtemperature overnight. To the reaction solution was added water, and themixture was distributed between ethyl acetate and water. The organiclayer was washed with an aqueous saturated sodium chloride solution, anddried. The solvent was distilled off, and the resulting oil wassubjected to silica gel column chromatography, and eluted withchloroform-methanol. Concentration of an objective fraction afforded 19mg of compound 527B as an oil.

MS: m/z=616 [M+H]⁺.

Second Step

Compound 527B (19 mg, 0.03 mmol) was dissolved in MeOH (0.6 mL), 10%Pd—C (3 mg) was added, and the mixture was subjected to a catalyticreduction reaction under hydrogen stream. The catalyst was removed byfiltration, and the filtrate was concentrated. The resulting oil wassubjected to diol silica gel column chromatography, and eluted withchloroform-methanol. Concentration of an objective fraction afforded 7mg of compound 527 as an oil.

MS: m/z=526 [M+H]⁺.

Using halides which are commercially available or known in thereferences and aldehydes which are commercially available or known inthe references, and according to the method of Reference example 527,compounds 528 to 531 were synthesized.

Reference Example 528

MS: m/z=418 [M+H]⁺

Reference Example 529

MS: m/z=432 [M+H]⁺

Reference Example 530

MS: m/z=459 [M+H]⁺

Reference Example 531

MS: m/z=466 [M+H]⁺

Reference Example 532

First Step

To a methanol (5 ml) solution of compound 519 (440 mg, 0.766 mmol) wasadded hydrazine hydrate (383 mg, 7.66 mmol), and the mixture wasrefluxed for 1 hour. After cooled to room temperature, the precipitatedinsolubles were filtered off. After the solvent was distilled off, theresidue was suspended in ethyl acetate, the insolubles were filteredoff, and the solvent was distilled off. The resulting crude product wassuspended in chloroform, and insolubles were filtered off. The solventwas distilled off, and the resulting crude product was washed with ethylacetate-diisopropyl ether to obtain 190 mg of compound 532 as a solid.

¹H-NMR (CDCl₃) δ: 1.24 (3H, d, J=6.9H), 1.46 (3H, d, J=6.6 Hz),2.73-2.90 (3H, m), 3.08 (1H, ddd, J=4.2 Hz, 12.9 Hz, 12.9 Hz), 3.54 (1H,ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 3.85-3.94 (1H, m), 4.19 (1H, dd, J=7.2Hz, 11.1 Hz), 4.35 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.97 (1H, s),5.74 (1H, d, J=7.5 Hz), 6.60 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.2 Hz),6.92 (1H, t, J=6.3 Hz), 7.09-7.45 (6H, m).

Reference Example 533

Compound 533 was synthesized by the same procedure as that of Referenceexample 532.

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, d, J=6.6 Hz), 1.40 (3H, d, J=6.6 Hz),0.1.45-1.58 (1H, m), 1.62-1.75 (1H, m), 2.61-2.69 (1H, m), 2.71-2.84(1H, m), 2.88-2.95 (1H, m), 3.16-3.34 (1H, m), 3.60-3.64 (1H, m),3.92-4.00 (1H, m), 4.24-4.33 (1H, m), 4.42-4.46 (1H, dd, J=3.3 Hz, 10.8Hz), 5.10 (1H, s), 5.47 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 6.88(1H, t, J=7.5 Hz), 7.02 (1H, d, J=10.8 Hz), 7.09-7.16 (2H, m), 7.19-7.25(1H, m), 7.33 (2H, d, 4.2 Hz), 7.42 (1H, d, J=7.5 Hz).

Reference Example 534

Compound 534 was synthesized by the same procedure as that of Referenceexample 532.

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, d, J=6.9 Hz), 1.44 (3H, d, J=6.6 Hz),1.32-1.58 (2H, m), 1.77-1.79 (2H, m), 2.64-2.73 (1H, m), 2.79-3.00 (2H,m), 3.88-3.97 (2H, m), 4.19-4.28 (2H, m), 5.15 (1H, s), 5.67 (1H, d,J=7.5 Hz), 5.73 (1H, d, J=7.5 Hz), 6.90 (1H, t, J=6.6 Hz), 7.03 (1H, d,J=7.5 Hz), 7.13-7.32 (3H, m), 7.36 (2H, d, J=4.2 Hz), 7.44 (1H, J=7.2Hz), 7.75 (1H, brs).

Reference Example 535

Compound 535 was synthesized by the same procedure as that of Referenceexample 532.

¹H-NMR (DMSO-d₆) δ: 1.40-1.52 (1H, m), 1.61-1.72 (1H, m), 2.40-2.49 (1H,m), 2.58-2.62 (1H, m), 2.78-2.86 (1H, m), 2.89-2.95 (1H, m), 2.95 (3H,m), 3.66-3.74 (1H, m), 4.01-4.13 (1H, m), 4.28-4.32 (1H, m), 5.14 (1H,m), 5.51 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=7.5 Hz), 6.91-6.94 (2H, m),7.14-7.40 (6H, m).

Reference Example 536

First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol)and a 38% aqueous formalin solution (53.5 mg, 0.675 mmol) was cooled to1 to 3° C., sodium triacetoxyhydroborate (42.9 mg, 0.293 mmol) andacetic acid (10 mg, 0.166 mmol) were added while the same temperaturewas retained. After the reaction solution was stirred at the sametemperature for 30 minutes, saturated sodium bicarbonate water wasadded, and the mixture was extracted with ethyl acetate three times. Thecombined extracts were washed with water once, and dried with sodiumsulfate, and the solvent was distilled off. The resulting crude productwas washed with ethyl acetate-diisopropyl ether to obtain 20 mg ofcompound 536 as a solid.

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=6.6 Hz), 1.44 (3H, d, J=6.9 Hz), 2.06(6H, s), 2.29 (1H, dd, J=4.5 Hz, 13.2 Hz), 4.23 (1H, dd, J=8.4 Hz, 13.2Hz), 2.78 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz, 3.06 (1H, J=4.2 Hz, 13.5Hz, 13.5 Hz), 3.55 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.83-3.92 (1H,m), 4.34 (1H, dd, J=4.5 Hz, 8.4 Hz), 4.54 (1H, ddd, J=4.5 Hz, 13.8 Hz,13.8 Hz), 4.91 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.8 Hz),6.64 (1H, d, J=7.8 Hz), 6.88-6.93 (1H, m), 7.08-7.45 (6H, m).

Reference Example 537

Compound 537 was synthesized by the same procedure as that of Referenceexample 536.

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, d, J=6.6 Hz), 1.40 (3H, d, J=6.6 Hz),1.46-1.57 (1H, m), 1.68-1.79 (1H, m), 1.98 (6H, s), 2.04-2.11 (1H, m),2.27-2.41 (1H, m), 2.72-2.94 (2H, m), 3.55-3.64 (1H, m), 3.91-4.00 (1H,m), 4.29-4.44 (2H, m), 5.10 (1H, s), 5.48 (1H, d, J=7.8 Hz), 6.71 (1H,d, J=7.8 Hz), 6.86-6.90 (1H, m), 7.05-7.24 (4H, m), 7.33 (2H, d, J=4.2Hz), 7.40 (1H, d, J=7.5 Hz).

Reference Example 538

Compound 538 was synthesized by the same procedure as that of Referenceexample 536.

¹H-NMR (DMSO-d₆) δ: 0.75 (6H, t, J=6.6 Hz), 1.28 (3H, d, J=6.6 Hz), 1.41(3H, d, J=6.6 Hz), 1.45-1.56 (1H, m), 1.67-1.78 (1H, m), 2.22-2.49 (4H,m), 2.74-2.97 (2H, m), 3.94-4.03 (1H, m), 4.29-4.41 (2H, m), 5.11 (1H,s), 5.48 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=6.9 Hz), 6.87 (1H, t, J=7.2Hz), 7.06-7.25 (4H, m), 7.33 (2H, d, J=7.2 Hz), 7.35 (1H, m).

Reference Example 539

Compound 539 was synthesized by the same procedure as that of Referenceexample 536.

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, d, J=6.6 Hz), 1.44 (3H, d, J=6.6 Hz),1.42-1.51 (2H, m), 1.75-1.91 (2H, m), 2.62-2.67 (1H, m), 2.65 (6H, s),2.74-2.97 (3H, m), 3.57-3.63 (1H, m), 3.91-3.26 (4H, m), 5.16 (1H, s),5.73 (1H, d, J=7.5 Hz), 6.71 (1H, d, J=7.2 Hz), 6.89 (1H, t, J=6.9 Hz),7.12-7.28 (4H, m), 7.33-7.45 (3H, m).

Reference Example 540

Compound 540 was synthesized by the same procedure as that of Referenceexample 536.

¹H-NMR (CDCl₃) δ: 1.58-1.78 (2H, m), 2.06 (6H, s), 2.15-2.35 (2H, m),2.84-2.93 (1H, m), 2.96-3.11 (1H, m), 3.00 (3H, s), 3.65-3.74 (1H, m),3.99-4.14 (1H, m), 4.28-4.33 (1H, m), 4.94 (1H, s), 5.78 (1H, d, J=7.5Hz), 6.56 (1H, d, J=7.8 Hz), 8.66 (1H, d, J=7.2 Hz), 6.95 (t, J=7.2 Hz),7.13-7.38 (6H, m).

Reference Example 541

Compound 541 was synthesized by the same procedure as that of Referenceexample 536.

¹H-NMR (CDCl₃) δ: 0.846 (6H, t, J=7.2 Hz), 1.49-1.75 (2H, m), 2.30-2.41(5H, m), 2.43-2.53 (1H, m), 2.85-2.93 (1H, m), 2.98-3.08 (1H, m), 3.01(3H, s), 3.63-3.74 (1H, m), 3.97-4.07 (1H, m), 4.30 (1H, dd, J=5.1 Hz,8.1 Hz), 4.95 (1H, s), 5.77 (1H, d, J=6.0 Hz), 6.56 (1H, d, J=7.8 Hz),6.65 (1H, d, J=7.8 Hz), 6.95 (1H, t, J=6.3 Hz), 7.13-7.38 (6H, m).

Reference Example 542

First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol)and triethylamine (20.5 mg, 0.202 mmol) was cooled to 1 to 3C, andacetic acid anhydride (10.3 mg, 0.101 mmol) was added while the sametemperature was retained. After the reaction solution was stirred at thesame temperature for 30 minutes, water was added, and the mixture wasextracted with ethyl acetate three times. The combined extracts werewashed with water once, and dried with sodium sulfate, and the solventwas distilled off. The resulting crude product was washed with ethylacetate-diisopropyl ether to obtain 15 mg of compound 542 as a solid.

¹H-NMR (CDCl₃) δ: 1.30 (3H, d, J=6.9 Hz), 1.47 (3H, d, J=6.6 Hz), 2.00(3H, s), 2.78-2.94 (2H, m), 3.04 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz),3.48-3.60 (1H, m), 3.98-3.07 (1H, m), 4.36 (1H, ddd, J=4.2 Hz, 13.5 Hz,13.5 Hz), 4.64 (1H, dd, J=3.9 Hz, 9.3 Hz), 4.87 (1H, s), 5.43 (1H, d,J=7.5 Hz), 6.57 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=7.5 Hz), 6.85 (1H, t,J=6.0 Hz), 7.09-7.36 (6H, m), 7.41 (1H, brs).

Reference Example 543

Compound 543 was synthesized by the same procedure as that of Referenceexample 542.

¹H-NMR (CDCl₃) δ: 1.32 (3H, d, J=6.9 Hz), 1.50 (3H, d, J=6.9 Hz), 2.79(1H, ddd, J=4.2 Hz, 4.2 Hz, 14.4 Hz), 3.01 (1H, ddd, J=3.9 Hz, 13.5 Hz,13.5 Hz), 3.18-3.28 (1H, m), 3.46-3.59 (2H, m), 4.04-4.18 (1H, m), 4.27(1H, ddd, J=3.9 Hz, 13.5 Hz, 13.5 Hz), 4.69 (1H, dd, J=3.3 Hz, 9.9 Hz),4.87 (0.9H, s), 5.17 (0.1H, s), 5.37 (0.9H, d, J=7.8 Hz), 4.50 (0.1H, d,J=7.8H), 6.32 (0.1H, d, J=7.8 Hz), 6.54 (1H, d, J=7.5 Hz), 6.78 (0.9H,d, J=7.5 Hz), 6.84 (1H, t, J=6.6 Hz), 6.91 (0.1H, d, J=6.0 Hz),7.06-7.51 (6H, m), 9.29 (1H, brs).

Reference Example 544

Compound 544 was synthesized by the same procedure as that of Referenceexample 542.

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.9 Hz), 1.46 (3H, d, J=6.3 Hz), 2.78(1H, ddd, J=4.5 Hz, 4.5 Hz, 15.9 Hz), 2.94-3.10 (2H, m), 3.19-3.54 (2H,m), 3.64 (3H, s), 3.96-3.11 (1H, m), 4.28 (1H, ddd, J=4.2 Hz, 13.5 Hz,13.5 Hz), 4.57 (1H, dd, J=3.3 Hz, 9.9 Hz), 4.91 (1H, s), 5.57 (1H, brs),5.70 (1H, d, J=7.5 Hz), 6.60 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.8 Hz),6.89 (1H, t, J=7.2 Hz), 7.08-7.47 (6H, m).

Reference Example 545

First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol)and pyridine (16 mg, 0.203 mmol) was cooled to 1 to 3° C., and2-methoxyacetyl chloride (11 mg, 0.101 mmol) was added while the sametemperature was retained. After the reaction solution was stirred at thesame temperature for 30 minutes, water was added, and the mixture wasextracted with ethyl acetate three times. The combined extracts werewashed with water once, and dried with sodium sulfate, and the solventwas distilled off. The resulting crude product was washed with ethylacetate-diisopropyl ether to obtain 22 mg of compound 545 as a solid.

¹H-NMR (CDCl₃) δ: 1.31 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.9 Hz), 2.77(1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 2.99-3.11 (2H, m), 3.47 (3H, s),3.47-3.55 (1H, m), 3.64-3.72 (1H, m), 3.77-3.88 (2H, m), 4.02-4.11 (1H,m), 4.23 (1H, ddd, J=4.2 Hz, 13.8 Hz, 13.8 Hz), 4.47 (1H, dd, J=3.3 Hz,9.9 Hz), 4.94 (1H, s), 5.75 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=9.0 Hz),6.67 (1H, 7.8 Hz), 6.80 (1H, brt), 6.91 (1H, t, J=7.5 Hz), 7.08-7.23(5H, m), 7.29-7.36 (1H, m).

Reference Example 546

First Step

To a dimethylformamide (1 ml) solution of 2-(methylthio)acetic acid(15.7 mg, 0.148 mmol) were added EDCI (28.5 mg, 0.148 mmol) and1-hydroxy benzotriazole (11.4 mg, 0.0742 mmol) at room temperature, themixture was stirred at the same temperature for 5 minutes, and compound532 was added. The reaction solution was stirred at room temperature for1 hour, and diluted with methanol (3 ml). The solution was cooled to 1to 3° C., a 2N aqueous sodium hydroxide solution (1 ml) was added, themixture was stirred at the same temperature for 30 minutes, and themixture was neutralized with 2N hydrochloric acid (1 ml). The reactionsolution was extracted with ethyl acetate three times, the combinedextracts were washed with water once, and dried with sodium sulfate, andthe solvent was distilled off. The resulting crude product was washedwith ethyl acetate-diisopropyl ether to obtain 15 mg of compound 546 asa solid.

¹H-NMR (CDCl₃) δ: 1.32 (3H, d, J=6.9 Hz), 1.50 (3H, J=6.6 Hz), 2.11 (3,s), 2.79 (1H, ddd, J=4.2 Hz, 4.2 Hz, 14.1 Hz), 2.99-3.16 (4H, m), 3.50(1H, ddd, J=4.5 Hz, 4.5 Hz, 12.9 Hz), 3.68 (1H, d, J=10.2 Hz), 3.97-4.11(1H, m), 4.26 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.94 (3H, s), 5.69(1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.8 Hz), 6.90(1H, t, J=6.0 Hz), 7.09 (1H, d, J=7.5 Hz), 7.20-7.25 (3H, m), 7.29-7.36(1H, m), 7.36-7.49 (1H, m).

Reference Example 547

First Step

To an acetic acid (3 ml) solution of compound 547A (367 mg, 0.812 mmol)synthesized by the same procedure as that of Reference example 516 anddibenzosuberol (205 mg, 0.974 mmol) was added dropwise sulfuric acid(0.6 ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and the mixture was extracted with ethyl acetate three times. Theextract was washed with water once, and dried with sodium sulfate, andthe solvent was distilled off. The resulting crude product was dissolvedin methanol (3 ml), a 2N aqueous sodium hydroxide solution (1 ml) wasadded at room temperature, and the mixture was stirred for 30 minutes.The reaction solution was neutralized with 2N aqueous hydrochloric acidsolution (1 ml), and extracted with ethyl acetate three times. Thecombined extracts were dried with sodium sulfate, and the solvent wasdistilled off. The resulting crude product was washed with ethylacetate-diisopropyl ether to obtain 75 mg of compound 547 as a solid.

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=6.9 Hz), 1.45 (3H, d, J=6.3 Hz), 2.80(1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H, m), 3.53 (1H, ddd,J=3.9 Hz, 3.9 Hz, 17.7 Hz), 3.64 (1H, dd, J=6.9 Hz), 12.3 Hz), 3.82 (1H,dd, J=3.3 Hz, 12.3 Hz), 3.86-3.97 (1H, m), 4.34-4.44 (2H, m), 4.88 (1H,s), 5.35 (1H, d, J=7.5 Hz), 6.52-6.58 (2H, m), 6.82 (1H, dt, J=1.8 Hz,7.2 Hz), 7.06-7.35 (6H, m).

Reference Example 548

Compound 548 was synthesized by the same procedure as that of Referenceexample 547.

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J=6.6 Hz), 1.50 (3H, d, J=6.6 Hz),1.70-1.81 (1H, m), 1.88-2.00 (1H, m), 2.85 (1H, ddd, J=4.5 Hz, 4.5 Hz,14.1 Hz), 2.99-3.11 (1H, m), 3.48-3.57 (1H, m), 3.68-3.73 (2H, m),3.83-3.92 (1H, m), 4.30 (1H, ddd, J=4.2 Hz, 13.8 Hz, 13.8 Hz), 4.54 (1H,dd, J=3.6 Hz, 11.1 Hz), 4.67 (1H, s), 5.69 (1H, d, J=7.8 Hz), 6.62 (1H,d, J=7.5 Hz), 6.64 (1H, d, J=5.7 Hz), 6.90 (1H, t, J=6.9 Hz), 7.07-7.36(6H, m).

Reference Example 549

First Step

To an acetic acid (3 ml) solution of compound 549A (997 mg, 1.69 mmol)synthesized by the same procedure as that of Reference example 516 anddibenzosuberol (1.07 g, 5.08 mmol) was added dropwise sulfuric acid (0.6ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and the mixture was extracted with ethyl acetate three times. Theextract was washed with water once, and dried with sodium sulfate, andthe solvent was distilled off. The resulting crude product was washedwith ethyl acetate-diisopropyl ether to obtain 513 mg of compound 549B.

¹H-NMR (CDCl₃) δ: 2.09 (3H, s), 2.71 (1H, ddd, J=3.6 Hz, 13.5 Hz, 13.5Hz), 3.18-3.27 (1H, m), 3.42-3.56 (2H, m), 3.80 (1H, dd, J=2.7 Hz, 14.1Hz), 4.03 (1H, dd, J=10.2 Hz, 14.1 Hz), 4.15 (1H, ddd, J=4.2 Hz, 4.2 Hz,9.3 Hz), 4.32-4.40 (1H, m), 4.49-4.53 (2H, m), 4.94 (1H, s), 5/83 (1H,d, J=7.8 Hz), 6.63 (1H, d, J=7.5 Hz), 6.69 (1H, d, J=7.8 Hz), 6.76 (1H,d, J=6.6 Hz), 6.91 (1H, t, J=7.5 Hz), 7.00 (1H, d, J=8.1 Hz), 7.12-7.17(2H, m), 7.20-7.32 (2H, m), 7.82-7.89 (4H, m).

Second Step

To a methanol (5 ml) solution of compound 549B (513 mg, 0.829 mmol) wasadded hydrazine hydrate (124.5 mg, 2.49 mmol), and the mixture wasrefluxed for 2 hours. After cooled to room temperature, to the reactionsolution were added 2N hydrochloric acid (30 ml) and ethyl acetate (30ml). After the layers were separated, the organic layer was extractedwith 2N hydrochloric acid two times. The combined aqueous layers wereneutralized with sodium bicarbonate water, and extracted withchloroform-methanol three times. The combined organic layers were driedwith sodium sulfate, and the solvent was distilled off. The resultingcrude product was washed with ethyl acetate-diisopropyl ether to obtain135 mg of compound 549.

¹H-NMR (DMSO-d₆) δ: 2.40-2.50 (1H, m), 2.72-2.80 (1H, m), 2.83-2.98 (2H,m), 3.03-3.66 (4H, m), 3.79-3.87 (1H, m), 4.11 (1H, 4.2 Hz), 4.32-4.44(1H, m), 5.12 (1H, s), 5.51 (1H, 7.5 Hz), 6.69 (d, J=7.5 Hz), 6.84-6.90(1H, m), 7.07-7.24 (4H, m), 7.30-7.34 (2H, m), 7.39-7.42 (1H, m).

Reference Example 550

According to Reference example 536, compound 550 was synthesized fromcompound 549 by the same procedure.

¹H-NMR (DMSO-d₆) δ: 0.77 (6H, t, 6.9 Hz), 1.99-2.36 (3H, m), 2.38-2.56(1H, m), 2.64 (1H, dd, J=3.9 Hz, 14.1 Hz), 2.75 z81H, ddd, J=4.5 Hz, 4.5Hz, 14.4 Hz), 2.89-3.00 (1H, m), 3.09-3.68 (4H, m), 3.74-3.82 (1H, m),4.09 (1H, brs), 4.17 (1H, dd, J=3.6 Hz, 8.4 Hz), 5.03 (1H, brs), 5.17(1H, s), 5.53 (1H, d, J=7.5 Hz), 6.73 (1H, d, J=7.5 Hz), 6.84 (1H, d,J=7.8 Hz), 6.91 (1H, t, J=7.2 Hz), 7.12-7.26 (4H, m), 7.31-7.44 (4H, m),7.45 (1H, d, J=7.2 Hz).

Reference Example 551

According to Reference example 536, compound 551 was synthesized fromcompound 549 by the same procedure.

¹H-NMR (DMSO-d₆) δ: 1.99 (6H, s), 2.27 (1H, brs), 2.51-2.27 (3H, m),3.56-3.70 (4H, m), 4.03 (2H, brs), 4.36 (1H, brs), 4.94 (2H, brs), 5.29(1H, brs), 6.54-6.83 (3H, m), 7.11-7.33 (6H, m).

Reference Example 552

First Step

To an acetic acid (2 ml) solution of compound 552A (137 mg, 0.367 mmol)synthesized by the same procedure as that of Reference example 516 anddibenzosuberol (386 mg, 1.83 mmol) was added dropwise sulfuric acid (0.4ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and the mixture was extracted with ethyl acetate three times. Theextract was washed with water once, and dried with sodium sulfate, andthe solvent was distilled off. The resulting crude product was dissolvedin methanol (5 ml), a 2N aqueous sodium hydroxide solution (2 ml) wasadded at room temperature, and the mixture was stirred for 30 minutes.The reaction solution was neutralized with 2N aqueous hydrochloric acidsolution (2 ml), and extracted with ethyl acetate two times. Thecombined extracts were dried with sodium sulfate, and the solvent wasdistilled off. The resulting crude product was washed with ethyl acetateto obtain 62 mg of compound 552.

¹H-NMR (CDCl₃) δ: 1.71-1.82 (1H, m), 2.09-2.21 (1H, m), 2.82-2.90 (1H,m), 3.06 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz), 3.19 (3H, s), 3.22-3.43(3H, m), 3.60 (1H, ddd, J=10.5 Hz, 10.5 Hz, 17.4 Hz), 3.79-3.96 (3H, m),4.12-4.21 (1H, m), 4.46 (1H, dd, J=3.3 Hz, 10.2 Hz), 4.98 (1H, s), 5.89(1H, d, J=7.5 Hz), 6.62 (1H, d, J=6.9 Hz), 6.64 (1H, d, J=7.5 Hz),6.88-6.93 (1H, m), 7.11-7.37 (6H, m).

Reference Example 553

Compound 553 was synthesized by the same procedure as that of Referenceexample 552.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.9 Hz),1.94-2.00 (1H, m), 2.82-2.90 (1H, m), 3.00-3.11 (1H, m), 5.31-3.59 (2H,m), 3.64-3.74 (1H, m), 3.94-4.04 (3H, m), 4.25-4.36 (1H, m), 5.04 (1H,s), 5.87 (1H, d, J=7.2 Hz), 6.65 (1H, d, J=7.2 Hz), 7.12 (1H, d, J=7.5Hz), 6.92 (1H, t, J=8.1 Hz), 7.10 (1H, d, J=7.2 Hz), 7.15-7.38 (5H, m).

Reference Example 554

First Step

To an acetic acid (2 ml) solution of compound 554A (100 mg, 0.177 mmol)synthesized by the same procedure as that of Reference example 516 anddibenzosuberol (186 mg, 0.885 mmol) was added dropwise sulfuric acid(0.4 ml) at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. The reaction solution was diluted withwater, and the mixture was extracted with ethyl acetate three times. Theextract was washed with water once, and dried with sodium sulfate, andthe solvent was distilled off. The resulting crude product was dissolvedin methanol (5 ml), a 2N aqueous sodium hydroxide solution (2 ml) wasadded at room temperature, and the mixture was stirred for 30 minutes.The reaction solution was neutralized with an aqueous citric acidsolution, and extracted with ethyl acetate two times. The combinedextracts were washed with sodium bicarbonate water, and dried withsodium sulfate, and the solvent was distilled off. The resulting crudeproduct was washed with ethyl acetate to obtain 24 mg of compound 554.

¹H-NMR (CDCl₃) δ: 2.81-2.91 (2H, m), 2.98-3.09 (1H, m), 3.60-3.75 (2H,m), 3.91-4.04 (2H, m), 4.08-4.17 (2H, m), 4.22-4.33 (2H, m), 4.80 (1H,s), 5.69 (1H, d, J=7.8 Hz), 6.48 (1H, d, J=7.5 Hz), 6.59 (1H, d, J=7.5Hz), 6.80-6.85 (1H, m), 7.13-7.35 (6H, m).

Reference Example 555

To an acetic acid (4 ml) solution of compound 555A (380 mg, 1.11 mmol)synthesized according to Reference example 516 and dibenzosuberol (1.16g, 5.52 mmol) was added dropwise sulfuric acid (0.8 ml) at roomtemperature, and the mixture was stirred at the same temperature for 30minutes. The reaction solution was diluted with water, and the mixturewas extracted with ethyl acetate three times. The extract was washedwith water once, and dried with sodium sulfate, and the solvent wasdistilled off. The resulting crude product was dissolved in methanol (5ml), a 2N aqueous sodium hydroxide solution (2 ml) was added at roomtemperature, and the mixture was stirred for 30 minutes. The reactionsolution was neutralized with an aqueous citric acid solution, andextracted with ethyl acetate three times. The combined extracts weredried with sodium sulfate, and the solvent was distilled off. To theresulting crude product were added ethyl acetate-diisopropyl ether, andthe precipitated residue was filtered to obtain 22 mg of compound 555.

¹H-NMR (CDCl₃) δ: 1.62 (3H, d, J=6.9 Hz), 2.81 (1H, ddd, J=4.2 Hz, 4.2Hz, 14.4 Hz), 3.09 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 3.37 (3H, s),3.37-3.53 (2H, m), 3.70 (1H, d, J=5.4 Hz), 4.23-4.30 (2H, m), 4.33-4.44(1H, m), 4.94 (1H, s), 5.70 (1H, d, J=7.8 Hz), 6.59 (1H, d, J=7.5 Hz),6.64 (1H, d, J=7.8 Hz), 6.88-6.92 (1H, m), 7.08-7.37 (6H, m).

Reference Example 556

According to Reference example 65 and Reference example 516, compound556 was synthesized by the same procedure.

¹H-NMR (CDCl₃) δ: 1.66-1.78 (2H, m), 1.97 (3H, s), 2.19-2.31 (1H, m),2.35-2.44 (1H, m), 2.49-2.57 (1H, m), 2.85-2.93 (1H, m), 3.06 (1H, J=3.9Hz, 12.9 Hz, 12.9 Hz), 3.27-3.39 (2H, m), 3.34 (3H, s), 3.58-3.73 (3H,m), 3.96-4.04 (1H, m), 4.08-4.18 (1H, m), 4.60 (1H, dd, J=3.0 Hz, 11.1Hz), 4.96 (1H, s), 6.52 (1H, d, J=7.5 Hz), 6.87-6.92 (1H, m), 7.18-7.28(4H, m), 7.31-7.40 (2H, m), 7.65 (1H, s), 12.04 (1H, s), 14.33 (1H, s).

Reference Example 557

Compound 557 was synthesized by the same procedure as that of Referenceexample 149.

MS: m/z=419 [M+H]⁺.

Reference Example 558

To a DMSO (2 mL) solution of compound 63B (68.8 mg, 0.120 mmol) wasadded copper chloride (39.2 mg, 0.396 mmol), and the mixture was stirredat 110° C. for 2 hours and, further, at 120° C. for 1 hour. Thereafter,copper chloride (50.0 mg, 0.505 mmol) was added, and the mixture wasstirred at 200° C. for 1 hour. The reaction solution was purified usingan LCMS fractionating device, the eluted solvent was distilled off, tothe concentrated residue was added diethyl ether, and the precipitatedwhite solid was filtered. Washing with diethyl ether, and dryingafforded 20.9 mg of compound 558.

MS: m/z=439 [M+H]⁺.

Reference Example 559

First Step

Compound 48A (43 mg, 0.083 mmol) was dissolved in dichloromethane (6.0mL), manganese dioxide (120 mg, 1.38 mmol) was added, and the mixturewas stirred at room temperature for 3 hours. After the reaction solutionwas filtered with celite, the filtrate was concentrated to obtain 22.3mg of compound 559B as a pale yellow solid.

¹HNMR (CDCl₃) δ: 3.17 (3H, s), 3.41-3.55 (4H, m), 3.95-4.07 (2H, m),4.28 (1H, d, J=16.1 Hz), 4.53 (1H, d, J=11.8 Hz), 5.49 (2H, d, J=2.0Hz), 6.97-7.66 (16H, m), 10.07 (1H, s).

Second Step

Compound 559B (22 mg, 0.043 mmol) was dissolved in THF (6.0 mL), a 40%methanamine methanol solution (6.5 ul, 0.064 mmol) and acetic acid (3.7ul, 0.064 mmol) were added, and the mixture was stirred at roomtemperature for 5 minutes. The reaction solution was ice-cooled,NaBH(OAc)₃ (14 mg, 0.064 mmol) was added, and the mixture was stirred atroom temperature overnight. To the reaction solution were added waterand chloroform, and the chloroform layer was separated. The aqueouslayer was extracted with chloroform, and sodium sulfate was added to thecombined extracts to dry them. The solvent was distilled off to obtain24 mg of compound 559C as a pale yellow solid.

MS: m/z=538 [M+H]⁺.

Third Step

Compound 559 was synthesized by the same procedure as that of Referenceexample 1.

MS: m/z=448 [M+H]⁺.

Reference Example 560

First Step

A dioxane (20 mL) mixed solution of (methoxymethyl)triphenylphosphoniumchloride (6.73 g, 19.0 mmol) was cooled to 0° C., and a 1.06M NaHMDStoluene solution (18.0 ml, 19.0 mmol) was added dropwise while the sametemperature was retained. After the reaction solution was stirred at thesame temperature for 30 minutes, compound 383A was added, and themixture was refluxed for 1 hour and 30 minutes. The reaction solutionwas returned to room temperature, and water and ethyl acetate wereadded. The ethyl acetate layer was separated, and the aqueous layer wasextracted with ethyl acetate. To the combined extracts was added sodiumsulfate to dry them. The solvent was distilled off, and the resultingoil was purified by silica gel column chromatography, and eluted withn-hexane-ethyl acetate (95:5, v/v). Concentration of an objectivefraction afforded 2.22 g of compound 560B as an oil.

¹H-NMR (CDCl₃) δ: 3.68 (3H, s), 3.73 (3H, s), 4.20 (4H, brs), 6.17 (1H,s), 6.39 (1H, s), 6.96-7.07 (6H, m), 7.18-7.32 (9H, m), 7.32-7.46 (1H,m).

Second Step

Compound 560B (1.98 g, 7.78 mmol) was dissolved in dichloromethane (30mL), a 70% aqueous perchloric acid solution (8.0 ml, 93 mmol) was added,and the mixture was stirred at room temperature overnight. To thereaction solution was added an aqueous saturated sodium carbonatesolution, and the dichloromethane layer was separated. The aqueous layerwas extracted with dichloromethane, and magnesium sulfate was added tothe combined extracts to dry them. The solvent was distilled off, andthe resulting oil was purified by silica gel column chromatography, andeluted with n-hexane-ethyl acetate (90:10, v/v). Concentration of anobjective fraction afforded 1.80 g of compound 560C as an oil.

¹H-NMR (CDCl₃) δ: 3.93 (1H, d, J=16.1 Hz), 4.06 (1H, d, J=16.1 Hz), 4.53(1H, s), 7.11-7.50 (8H, m), 9.89 (1H, s).

MS: m/z=241 [M+H]⁺.

Third Step

To a dichloromethane (30 mL) solution of compound 560C (2.87 g, 11.9mmol) were added tetraisopropoxytitanium (17.5 mL, 59.7 mmol) and(S)-4-methylbenzenesulfinamide (2.27 g, 14.3 mmol) at room temperature,then the mixture was refluxed for 3 hours and 30 minutes. The reactionsolution was ice-cooled, ice water (30 ml) was added, the mixture wasstirred for 1 hour while temperature was retained at the sametemperature, and the precipitated solid was filtered using celite. Theresulting filtrate was extracted with dichloromethane, and magnesiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, and the resulting oil was purified by silica gel columnchromatography, and eluted with n-hexane-ethyl acetate (70:30, v/v).Concentration of an objective fraction afforded 3.16 g of compound 560Das a yellow solid.

¹H-NMR (CDCl₃) δ: 2.39 (6H, s), 3.60 (1H, d, J=15.2 Hz), 3.68 (1H, d,J=14.9 Hz), 3.97 (1H, d, J=15.0 Hz), 4.07 (1H, d, J=15.0 Hz), 4.90 (1H,d, J=2.7 Hz), 4.92 (1H, d, J=2.9 Hz), 7.08-7.26 (20H, m), 7.46-7.51 (4H,m), 8.62 (1H, d, J=2.8 Hz), 8.65 (1H, d, J=2.7 Hz).

MS: m/z=378 [M+H]⁺.

Fourth Step

A THF (30 mL) suspension of a 1M cyanodiethylaluminum toluene solution(16.7 mL, 16.7 mmol) was cooled to 0° C., 2-propanol (1.29 mL, 16.7mmol) was added and, thereafter, the mixture was stirred for 1 hourwhile temperature was retained at the same temperature. Thereafter, thereaction solution was cooled to −60° C., a THF (12 mL) solution ofcompound 560D (3.16 g, 8.37 mmol) was added dropwise, the mixture wasstirred for 15 minutes while temperature was retained at the sametemperature, thereafter, temperature was raised to room temperature, andthe mixture was stirred overnight. The reaction solution was ice-cooled,an aqueous saturated ammonium chloride solution was added, the mixturewas stirred at room temperature for 1 hour and 30 minutes and,thereafter, the precipitated solid was filtered using celite, and washedwith dichloromethane. The dichloromethane layer of the filtrate wasseparated, and the aqueous layer was extracted with dichloromethane and,thereafter, sodium sulfate was added to the combined extracts to drythem. The solvent was distilled off, and the resulting oil was purifiedby silica gel column chromatography, and eluted with chloroform-methanol(97:3, v/v). Concentration of an objective fraction afforded 1.88 g ofcompound 560E as a white solid.

MS: m/z=427 [M+Na]⁺.

Fifth Step

A methanol (4 mL) solution of compound 560E (235 mg, 0.581 mmol) wascooled to 0° C., cobalt(II) chloride hexahydrate (55.3 mg, 0.232 mmol)was added, and the mixture was stirred at room temperature for 30minutes. Thereafter, the reaction solution was ice-cooled, a DMF (4 mL)solution of sodium borohydride (88 mg, 2.3 mmol) was added dropwise, andthe mixture was stirred at the same temperature for 5 minutes, and atroom temperature for 1 hour. Then, Boc₂O (0.674 mL, 2.90 mmol) wasadded, and the mixture was stirred for 30 minutes. To the reactionsolution was added water, the mixture was extracted with ethyl acetate,and sodium sulfate was added to the combined extracts to dry them. Thesolvent was distilled off, and the resulting oil was subjected to silicagel column chromatography, and eluted with chloroform-methanol (98:2,v/v). Concentration of an objective fraction afforded a crude product(211 mg) of compound 560F.

MS: m/z=509 [M+Na]⁺.

Sixth Step

To a methanol (6 mL) solution of the crude product (211 mg) of compound560F was added TFA (0.128 mL, 1.66 mmol), and the mixture was stirred atroom temperature for 2.5 hours. To the reaction solution was addedtriethylamine (0.230 mL, 1.66 mmol), the solvent was distilled off, andthe resulting crude product of compound 560G was used in a next reactionwithout purification.

MS: m/z=371 [M+H]⁺.

Seventh Step

To a toluene (4 mL) solution of the crude product of compound 560G wasadded dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (132 mg,0.416 mmol), and the mixture was refluxed for 1 hour and 30 minutes. Thereaction solution was subjected to silica gel column chromatography, andeluted with chloroform-methanol (100:0→90:10, v/v). Concentration of anobjective fraction afforded a crude product (287 mg) of compound 560H.

MS: m/z=671 [M+H]⁺.

Eighth Step

To the crude product of compound 560H obtained in the seventh step wasadded a 4N hydrochloric acid ethyl acetate solution (3 mL), and themixture was stirred at room temperature for 30 minutes. The solvent wasdistilled off, to the resulting concentrated residue were added THF (2mL) and an aqueous saturated sodium bicarbonate solution (2 mL), and themixture was stirred at room temperature for 45 minutes. To the reactionsolution was added water, the mixture was extracted with chloroform, andsodium sulfate was added to the combined extracts to dry them. Thesolvent was distilled off, and the resulting oil was subjected to silicagel column chromatography, and eluted with chloroform-methanol(100:0→94:6, v/v). Concentration of an objective fraction afforded 27 mgof compound 5601 as a yellow solid.

MS: m/z=539 [M+H]⁺.

Ninth Step

Compound 5601 (27 mg, 0.050 mmol) was dissolved in DMF (2 mL), cesiumcarbonate (82 mg, 0.25 mmol) and methyl iodide (0.010 mL, 0.16 mmol)were added, and the mixture was stirred at room temperature for 1 hourand 30 minutes. To the reaction solution was added water, the mixturewas extracted with ethyl acetate, and sodium sulfate was added to thecombined extracts to dry them. The solvent was distilled off, and theresulting oil was subjected to silica gel column chromatography, andeluted with chloroform-methanol (100:0→94:6, v/v). Concentration of anobjective fraction afforded a crude product of compound 560J.

MS: m/z=553 [M+H]⁺.

Tenth Step

To an EtOH (2 mL) solution of the crude product of compound 560Jobtained in the ninth step was added 2N NaOH (1 mL), and the mixture wasstirred at room temperature for 40 minutes. To the reaction solution wasadded a 2N aqueous HCl solution, the mixture was extracted with ethylacetate, and sodium sulfate was added to the combined extracts to drythem. The solvent was distilled off to obtain 17 mg of compound 560K asa white oil.

MS: m/z=539 [M+H]⁺.

Eleventh Step

To compound 560K (17 mg, 0.032 mmol) was added TFA (2.0 mL), and themixture was stirred at room temperature for 35 minutes. The reactionsolution was subjected to toluene azeotropy, to the resultingconcentrated residue was added isopropyl ether, and the precipitatedsolid was filtered and washed to obtain 7.1 mg of compound 560 as a pinksolid.

MS: m/z=449 [M+H]⁺.

Reference Example 561

First Step

To a crude product (433 mg) of compound 560H was added a 4N hydrochloricacid ethyl acetate solution (3 mL), and the mixture was stirred at roomtemperature for 1 hour. The solvent was distilled off, to a THF (2 mL)solution of the resulting residue was added acetone (2 mL), the mixturewas stirred at room temperature for 20 minutes, NaBH(OAc)₃ (70 mg, 0.32mmol) was added, and the mixture was stirred at room temperature for 1hour and 30 minutes. Thereafter, to the reaction solution was added anaqueous saturated sodium bicarbonate solution (3 mL), and the mixturewas stirred at room temperature overnight. To the reaction solution wasadded water, the mixture was extracted with chloroform, and sodiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, and the resulting oil was subjected to silica gel columnchromatography, and eluted with chloroform-methanol (100:0→94:6, v/v).Concentration of an objective fraction afforded a crude product (79 mg)of compound 561A.

MS: m/z=581 [M+H]⁺.

Second Step

To an EtOH (4 mL) solution of the crude product (79 mg) of compound 561Awas added 2N NaOH (2 mL), and the mixture was stirred at roomtemperature for 1 hour. To the reaction solution was added a 2N aqueousHCl solution, the mixture was extracted with ethyl acetate, and sodiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, and the resulting oil was subjected to silica gel columnchromatography, and eluted with chloroform-methanol (100:0→94:6, v/v).Concentration of an objective fraction afforded compound 561B (53 mg).

MS: m/z=567 [M+H]⁺.

Third Step

A DMF (2 mL) solution of compound 561B (53 mg, 0.093 mmol) was cooled to0° C., triethylamine (0.039 mL, 0.28 mmol) and ethyl chloroformate(0.018 mL, 0.187 mmol) were added, and the mixture was stirred at roomtemperature for 10 minutes. Thereafter, the reaction solution was cooledto 0° C., sodium azide (18 mg, 0.28 mmol) was added, and the mixture wasstirred for 50 minutes while temperature was retained at the sametemperature. To the reaction solution was added water, the mixture wasextracted with dichloromethane, and the combined extracts wereconcentrated to obtain a crude product of compound 561C.

MS: m/z=592 [M+H]⁺.

Fourth Step

The crude product (55 mg) of compound 561C was dissolved in methanol (2mL), and the mixture was stirred at 50° C. for 1 hour. The reactionsolution was subjected to silica gel column chromatography, and elutedwith chloroform-methanol (100:0→94:6, v/v). Concentration of anobjective fraction afforded a crude product (43 mg) of compound 561D.

MS: m/z=596 [M+H]⁺.

Fifth Step

To an EtOH (2 mL) solution of the crude product (43 mg) of compound 561Dwas added 2N NaOH (4 mL), and the mixture was stirred at 60° C. for 1hour. The solvent was distilled off, water was added, the mixture wasextracted with ethyl acetate and, thereafter, sodium sulfate was addedto the combined extracts to dry them. The solvent was distilled off, theresulting oil was subjected to amino column chromatography, and elutedwith chloroform-methanol (100:0→80:20, v/v). Concentration of anobjective fraction afforded 16 mg of compound 561E as a pale yellowsolid.

MS: m/z=538 [M+H]⁺.

Sixth Step

Compound 561E (16 mg, 0.029 mmol) was dissolved in EtOH (1 mL) and a 48%aqueous tetrafluoroboric acid (1 mL), the reaction solution was cooledto 0° C., sodium nitrite (15 mg, 0.22 mmol) was added, and the mixturewas stirred for 1 hour and 30 minutes while temperature was retained atthe same temperature and, further, at room temperature for 2 hours and30 minutes. To the reaction solution was added water, the mixture wasextracted with chloroform, and sodium sulfate was added to the combinedextracts to dry them. The solvent was distilled off, to the resultingconcentrated residue were added ethyl acetate and isopropyl ether, andthe precipitated solid was filtered and washed to obtain 5 mg ofcompound 561 as a white solid.

¹H-NMR (CDCl₃) δ: 0.96 (3H, d, J=6.9 Hz), 1.17 (3H, d, J=6.8 Hz), 3.37(1H, d, J=13.3 Hz), 3.88 (1H, dd, J=13.4, 4.3 Hz), 3.99 (1H, d, J=14.9Hz), 4.08 (1H, d, J=11.3 Hz), 4.52 (1H, d, J=14.9 Hz), 4.81-4.90 (1H,m), 5.67 (1H, dd, J=11.3, 3.1 Hz), 5.94 (1H, d, J=7.4 Hz), 6.59 (1H, d,J=6.4 Hz), 6.72 (1H, d, J=7.3 Hz), 6.86 (1H, t, J=7.1 Hz), 7.09 (1H, t,J=7.6 Hz), 7.16-7.31 (5H, m).

Reference Example 562

Compound 562 was synthesized by the same procedure as that of Referenceexample 561.

¹H-NMR (CDCl₃) δ: 3.07 (3H, s), 3.21 (1H, d, J=12.3 Hz), 4.00-4.31 (4H,m), 5.78 (1H, d, J=10.5 Hz), 5.94 (1H, d, J=7.4 Hz), 6.54 (1H, d, J=7.3Hz), 6.69 (1H, d, J=7.5 Hz), 6.98 (1H, t, J=7.6 Hz), 7.14-7.41 (6H, m).

MS: m/z=405 [M+H]⁺.

Reference Example 563

First Step

Compound 563A (Tetrahedron Letters, 34, 953-956, 1993, 41.1 g, 154 mmol)was dissolved in THF (300 mL), 1M BH₃-THF (770 mL) was slowly added atroom temperature, and the mixture was stirred for 18 hours. 3N aqueoushydrochloric acid solution (513 mL) was slowly added, and the mixturewas refluxed for 1 hour, and was progressed to a next step withoutpurification.

LC-MS: m/z=254 [M+H]⁺.

Second Step

Using a solution containing compound 563B, according to Referenceexample 12, compound 563C was synthesized.

LC-MS: m/z=353 [M+H]⁺.

¹H-NMR (DMSO-d₆): 1.40 (9H, s), 2.65-2.72 (1H, m), 2.86-2.92 (3H, m),3.47-3.56 (3H, m), 3.56-3.69 (1H, m), 6.63 (1H, s), 7.11-7.26 (8H, m).

Third Step

A toluene (30 mL) solution of compound 563C (2.16 g, 6.79 mmol) anddimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (2.38 g, 6.75mmol) was stirred at 100° C. for 4 hours. The reaction solution wasdistilled off under reduced pressure, and the resulting crude product ofcompound 563D was used in a next reaction without purification.

MS: m/z=653.05 [M+H]⁺.

Fourth Step

To an ethyl acetate (20 mL) solution of the crude product of compound563D was added hydrogen chloride (4N ethyl acetate solution, 20 mL) atroom temperature, and the mixture was stirred for 30 minutes. Thereaction solution was distilled off under reduced pressure, and theresulting crude product of compound 563E was used in a next reactionwithout purification.

MS: m/z=553.05 [M+H]⁺.

Fifth Step

To a tetrahydrofuran (40 mL) solution of the crude product of compound563E was added saturated sodium bicarbonate water (5 mL) at roomtemperature, and the mixture was stirred for 16 hours. To the reactionsolution was added water (50 mL), the mixture was extracted withchloroform three times, and the extracts were combined, and dried withsodium sulfate. The solvent was distilled off under reduced pressure,and diethyl ether and chloroform were added to the resulting residue tocovert them into a powder, to obtain compound 563F (2.90 g, 70.2%) as awhite solid.

MS: m/z=521.05 [M+H]⁺.

Sixth Step

To a methanol (7.5 mL) suspension of compound 563F (523 mg, 1.01 mmol)was added an aqueous sodium hydroxide solution (2M, 1.5 mL) at roomtemperature, and the mixture was stirred for 3 hours. To the reactionsolution were added hydrochloric acid (2N, 1.5 mL) and water (3 mL) atroom temperature and, thereafter, the mixture was stirred at 0° C. for15 minutes. The precipitated solid was filtered, and washed with waterand diethyl ether to obtain compound 563G (418 mg, 82.0%) as a whitesolid.

MS: m/z=507.00 [M+H]⁺.

Seventh Step

A diphenyl ether (5 mL) suspension of compound 563G (107 mg, 0.211 mmol)was stirred at 240° C. for 1 hour under microwave irradiation. Thereaction solution was purified by silica gel column chromatography(methanol/chloroform=0%→5%) to obtain compound 563H (64.4 mg, 65.9%) asa white solid.

MS: m/z=463.05 [M+H]⁺.

Eighth Step

A methanol (30 mL) solution of compound 563H (64.4 mg, 0.139 mmol) washydrogenated by passing through 10% Pd—C CatCart (H-cube, Full-H₂ mode,25° C.) for 3 hours. The reaction solution was distilled off underreduced pressure, and ethyl acetate and methanol were added to theresulting residue to convert it into a powder, to obtain compound 563(31.1 mg, 60.0%) as a gray white solid.

¹HNMR (DMSO-d₆) δ: 2.50-3.03 (3H, m), 3.50-3.72 (3H, m), 4.29 (1H, d,J=11.4 Hz), 5.12 (1H, m), 5.69 (1H, d, J=7.2 Hz), 6.50 (1H, d, J=7.7Hz), 6.75 (1H, d, J=7.7 Hz), 6.84 (1H, m), 7.14-7.30 (6H, m), 9.16 (1H,d, J=4.8 Hz).

MS: m/z=372.90 [M+H]⁺.

Reference Example 564

First Step

To a dimethylformamide (2 mL) suspension of compound 563H (64.2 mg,0.139 mmol) and cesium carbonate (220 mg, 0.675 mmol) was added methyliodide (0.0430 mL, 0.688 mmol) at room temperature, and the mixture wasstirred for 3 hours. To the reaction solution was added water (10 mL) atroom temperature, and the mixture was extracted with ethyl acetate (30mL). The organic layer was washed with water (10 mL) and an aqueoussaturated sodium chloride solution (10 mL), and dried with sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography(methanol/chloroform=2.5%→10%) to obtain compound 564A (56.0 mg, 85.0%)as a colorless gummy substance.

MS: m/z=477.00 [M+H]⁺.

Second Step

A solution of compound 564A (56.0 mg, 0.118 mmol) in methanol (10 mL),ethyl acetate (5 mL) and tetrahydrofuran (5 mL) was hydrogenated bypassing through 10% Pd—C CatCart (H-cube, Full-H₂ mode, 25° C.) for 75minutes. The reaction solution was distilled off under reduced pressure,and ethyl acetate and methanol were added to the resulting residue toconvert it into a powder, to obtain compound 564 (22.0 mg, 48.4%) as agray white solid.

¹HNMR (DMSO-d₆) δ: 2.86-2.98 (6H, m), 3.51-3.58 (2H, m), 3.94 (1H, m),4.30 (1H, d, J=11.1 Hz), 5.19 (1H, d, J=10.2 Hz), 5.79 (1H, d, J=6.9Hz), 6.49 (1H, d, J=7.4 Hz), 6.74 (1H, d, J=7.4 Hz), 6.85 (1H, m), 7.14(2H, m), 7.25 (4H, m), 12.50 (1H, brs).

MS: m/z=387.05 [M+H]⁺.

Reference Example 565

Compound 565 was synthesized by the same procedure as that of Referenceexample 564.

MS: m/z=443.95 [M+H]⁺.

Reference Example 566

First Step

A dimethylformamide (2 mL) suspension of compound 563H (75.4 mg, 0.163mmol), 3-iodobenzonitrile (124 mg, 0.541 mmol), copper(I) iodide (33.2mg, 0.174 mmol), potassium carbonate (74.7 mg, 0.540 mmol) andN,N′-dimethylethylenediamine (0.0200 ml, 0.186 mmol) was stirred at 140°C. for 2 hours under microwave irradiation. To the reaction solutionwere added water (10 mL) and hydrochloric acid (2M, 2 mL) at roomtemperature, and the mixture was extracted with ethyl acetate. Theextract was filtered with celite, and the filtrate was washed with water(10 mL×2) and an aqueous saturated sodium chloride solution (10 mL), anddried with sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting crude product of compound 566A was used in anext reaction without purification.

MS: m/z=564.05 [M+H]⁺.

Second Step

To a methylene chloride (10 mL) solution of the crude product ofcompound 566A obtained in the first step was added trifluoroacetic acid(2 mL) at room temperature, and the mixture was stirred for 1 hour. Thereaction solution was concentrated under reduced pressure, and theresulting residue was purified by preparative LCMS to obtain compound566 (30.3 mg, 39.3%) as a yellow solid.

¹HNMR (DMSO-d₆) δ: 2.81-2.94 (2H, m), 3.38-3.58 (2H, m), 4.54 (1H, d,J=10.5 Hz), 4.64 (1H, d, J=10.5 Hz), 5.35 (1H, d, J=10.5 Hz), 5.76 (1H,m), 6.66-6.71 (3H, m), 6.90 (1H, m), 7.06-7.15 (6H, m), 7.76 (2H, m),7.90 (2H, m).

MS: m/z=473.90 [M+H]⁺.

Reference Example 567

Compound 567 was synthesized by the same procedure as that of Referenceexample 566.

¹HNMR (DMSO-d₆) δ: 2.80-3.00 (2H, m), 3.40-3.70 (2H, m), 4.52 (1H, m),4.64 (1H, m), 5.38 (1H, m), 5.76 (1H, m), 6.60-7.20 (10H, m), 7.60-7.90(3H, m), 8.11 (1H, m).

MS: m/z=474.00 [M+H]⁺.

Reference Example 568

Compound 568 was synthesized by the same procedure as that of Referenceexample 566.

¹HNMR (DMSO-d₆) δ: 2.87-2.96 (2H, m), 3.34-3.73 (2H, m), 4.64 (2H, m),5.33 (1H, m), 5.71 (1H, d, J=7.2 Hz), 6.61 (1H, d, J=7.8 Hz), 6.87-6.95(3H, m), 7.00-7.27 (6H, m), 7.62 (2H, m), 7.86 (1H, m), 8.07 (1H, m).

MS: m/z=474.00 [M+H]⁺.

Reference Example 569

Compound 569 was synthesized by the same procedure as that of Referenceexample 566.

MS: m/z=449.95 [M+H]⁺.

Reference Example 570

Compound 570 was synthesized by the same procedure as that of Referenceexample 566.

¹HNMR (DMSO-d₆) δ: 2.83-2.97 (3H, m), 3.16-3.62 (2H, m), 3.56 (1H, m),3.66 (1H, d, J=11.1 Hz), 5.35 (1H, d, J=11.1 Hz), 5.73 (1H, d, J=7.4Hz), 6.68 (1H, d, J=7.4 Hz), 6.92 (1H, m), 7.06-7.21 (5H, m), 7.49 (1H,m), 7.97 (1H, d, J=8.4 Hz), 8.14 (1H, s), 8.50 (1H, d, J=3.6 Hz), 8.81(1H, d, J=2.1 Hz).

MS: m/z=449.95 [M+H]⁺.

Reference Example 571

First Step

To a DMF (1 mL) solution of compound 563H (50.0 mg, 0.108 mmol) wasadded cesium carbonate (176 mg, 0.540 mmol), and the mixture was stirredat room temperature for 10 minutes. To the reaction solution was addedO-(2,4-dinitrophenyl)hydroxylamine (64.6 mg, 0.324 mmol), and themixture was stirred at room temperature for 9 hours. To the reactionsolution was added chloroform, and the mixture was washed with water,and dried with sodium sulfate. The solvent was distilled off, and theresulting oil was purified by silica gel column chromatography. Thematerials were eluted firstly with chloroform and, then, withchloroform-methanol (98:2, v/v). Concentration of an objective fractionafforded 28.3 mg of compound 571A as an amorphous substance.

MS: m/z=478 [M+H]⁺.

Second Step

Compound 571A (27.0 g, 0.057 mmol) was dissolved in a THF-methanol (1mL, 1:1, v/v) solution, 10% palladium carbon (15.0 mg) was added, andthe mixture was stirred at room temperature for 2 hours under hydrogenatmosphere. After dilution with chloroform, insolubles were removed bycelite filtration. After the filtrate was concentrated under reducedpressure, the residue was solidified with dichloromethane-ether toobtain 12.0 mg of compound 571.

MS: m/z=388 [M+H]⁺.

Reference Example 572

Using compound 12H, and according to Reference example 571, compound 572was synthesized by the same procedure.

MS: m/z=420 [M+H]⁺.

Reference Example 573

First Step

To a dimethylformamide (1.5 mL) solution of compound 563H (83.2 mg,0.160 mmol) was added sodium hydride (60%, 13.2 mg, 0.330 mmol) underice-cooling, the mixture was stirred for 30 minutes, thereafter,bromoacetonitrile (0.0190 mL, 0.270 mmol) was added, and the mixture wasstirred at room temperature for 1 hour. To the reaction solution wasadded an aqueous ammonium chloride solution (10%, 3 mL), and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater (10 mL) and an aqueous saturated sodium chloride solution (10 mL),and dried with sodium sulfate. The solvent was distilled off underreduced pressure, and the resulting crude product of compound 573A wasused in a next reaction without purification.

MS: m/z=502.00 [M+H]⁺.

Second Step

To an acetonitrile (4 mL) suspension of the crude product of compound573A obtained in the first step and sodium iodide (111 mg, 0.741 mmol)was added chlorotrimethylsilane (0.0920 mL, 0.720 mmol) at roomtemperature, and the mixture was stirred for 24 hours. To the reactionsolution was added an aqueous sodium hydrogen sulfite solution (10%, 10mL) and, thereafter, the mixture was extracted with chloroform. Afterthe extracts were combined, and dried with sodium sulfate, the solventwas concentrated under reduced pressure, and the resulting residue waspurified by preparative LCMS to obtain compound 573 (22.0 mg, 29.7%) asa gray white solid.

¹H-NMR (DMSO-d₆) δ: 2.86-2.95 (2H, m), 3.45-3.63 (2H, m), 4.01 (1H, m),4.30 (1H, d, J=10.8 Hz), 4.35 (1H, d, J=17.4 Hz), 4.74 (1H, d, J=17.4Hz), 5.20 (1H, m), 5.66 (1H, d, J=7.5 Hz), 6.52 (1H, d, J=7.8 Hz), 6.73(1H, d, J=7.5 Hz), 6.83 (1H, m), 7.11-7.28 (6H, m).

MS: m/z=502.00 [M+H]⁺.

Reference Example 574

Compound 574 was synthesized by the same procedure as that of Referenceexample 573.

¹H-NMR (DMSO-d₆) δ: 4.16 (1H, dd, J=13.26, 3.53 Hz), 4.36 (1H, d,J=11.58 Hz), 4.52 (2H, dd, J=20.73, 17.54 Hz), 5.44 (1H, d, J=11.41 Hz),5.65 (1H, d, J=7.39 Hz), 6.99 (1H, d, J=7.55 Hz), 7.11-7.32 (6H, m),7.36-7.45 (2H, m), 7.58 (2H, d, J=7.39 Hz).

Reference Example 575

Compound 575 was synthesized by the same procedure as that of Referenceexample 573.

MS: m/z=425.95 [M+H]⁺.

Reference Example 576

First Step

A dichloromethane (30 mL) solution of compound 576A (Bioorg. Med. Chem.,2003, 11, 197-206) (2.26 g, 10.2 mmol) were addedtetraisopropoxytitanium (10.0 mL, 33.1 mmol) and(S)-4-methylbenzenesulfinamide (1.29 g, 8.13 mmol) at room temperature,and the mixture was refluxed for 2 hours. The reaction solution wasice-cooled, ice water (40 ml) was added, the mixture was stirred for 1hour while temperature was retained at the same temperature, and theprecipitated solid was filtered using celite. The resulting filtrate wasextracted with dichloromethane, and magnesium sulfate was added to thecombined extracts to dry them. The solvent was distilled off, and theresulting oil was purified by silica gel column chromatography, andeluted with n-hexane-ethyl acetate (100:0→70:30, v/v). Concentration ofan objective fraction afforded 1.35 g of compound 576B as a yellowsolid.

¹H-NMR (CDCl₃) δ: 2.32 (3H, s), 2.72-2.85 (2H, m), 3.03-3.16 (2H, m),4.89 (1H, d, J=3.5 Hz), 7.09-7.25 (10H, m), 7.39-7.42 (2H, m), 8.49 (1H,d, J=3.6 Hz).

MS: m/z=360 [M+H]⁺.

Second Step

A THF (20 mL) solution of a 1M cyanodiethylaluminum toluene solution(7.51 mL, 7.51 mmol) was cooled to 0° C., 2-propanol (0.579 mL, 7.51mmol) was added and, thereafter, the mixture was stirred for 1 hourwhile temperature was retained at the same temperature. Thereafter, thereaction solution was cooled to −60° C., a THF (14 mL) solution ofcompound 576B was added dropwise, the mixture was stirred for 15 minuteswhile temperature was retained at the same temperature, thereafter,temperature was raised to room temperature, and the mixture was stirredovernight. The reaction solution was ice-cooled, an aqueous saturatedammonium chloride solution was added, the mixture was stirred at roomtemperature for 1 hour and 30 minutes and, thereafter, the precipitatedsolid was filtered using celite, and washed with dichloromethane. Thedichloromethane layer of the filtrate was separated, and the aqueouslayer was extracted with dichloromethane and, thereafter, sodium sulfatewas added to the combined extracts to dry them. The solvent wasdistilled off, to the resulting oil were added ethyl acetate and hexane,and the precipitated solid was filtered and washed to obtain 976 mg ofcompound 576C as a white solid.

¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 2.92-3.055 (2H, m), 3.41-3.52 (2H, m),4.25 (1H, d, J=10.8 Hz), 4.28 (1H, d, J=5.6 Hz), 4.94 (1H, dd, J=10.6,5.7 Hz), 7.14-7.41 (12H, m).

Third Step

A methanol (8 mL) suspension of compound 576C (500 mg, 1.29 mmol) wascooled to 0° C., cobalt(II) chloride hexahydrate (123 mg, 0.517 mmol)was added, and the mixture was stirred at room temperature for 30minutes. To the reaction solution was added chloroform (5 mL),thereafter, the mixture was ice-cooled, a DMF (4 mL) solution of sodiumborohydride (196 mg, 5.17 mmol) was added dropwise, and the mixture wasstirred at the same temperature for 5 minutes, and at room temperaturefor 2 hours. Then, Boc₂O (1.0 mL, 4.3 mmol) was added, and the mixturewas stirred at room temperature overnight. To the reaction solution wasadded water, the mixture was extracted with ethyl acetate, and sodiumsulfate was added to the combined extracts to dry them. The solvent wasdistilled off, and the resulting oil was subjected to silica gel columnchromatography, and eluted with chloroform-methanol (100:0→98:2, v/v).Concentration of an objective fraction afforded a crude product (200 mg)of compound 576D.

MS: m/z=491 [M+Na]⁺.

Fourth Step

To a methanol (6 mL) solution of the crude product (200 mg) of compound576D obtained in the third step was added TFA (0.188 mL, 2.45 mmol), andthe mixture was stirred at room temperature for 2.5 hours. To thereaction solution was added triethylamine (0.399 mL, 2.45 mmol), thesolvent was distilled off, and the resulting crude product of compound576E was used in a next reaction without purification.

MS: m/z=353 [M+H]⁺.

Fifth Step

To a toluene (4 mL) solution of the crude product of compound 576Eobtained in the fourth step was added dimethyl3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (130 mg, 0.409 mmol), andthe mixture was refluxed for 2 hours. The reaction solution wassubjected to silica gel column chromatography, and eluted withchloroform-methanol (100:0→90:10, v/v). Concentration of an objectivefraction afforded a crude product (268 mg) of compound 576F.

MS: m/z=653 [M+H]⁺.

Sixth Step

To the crude product (263 mg) of compound 576F obtained in the fifthstep was added a 4N hydrochloric acid ethyl acetate solution (3 mL), andthe mixture was stirred at room temperature for 1 hour and 30 minutes.The solvent was distilled off, to a THF (4 mL) solution of the resultingconcentrated residue was added acetone (1 mL), the mixture was stirredat room temperature for 25 minutes, thereafter, NaBH(OAc)₃ (180 mg,0.807 mmol) was added, and the mixture was stirred at room temperaturefor 1 hour and 15 minutes. Thereafter, to the reaction solution wasadded an aqueous saturated sodium bicarbonate solution (7 mL), and themixture was stirred at room temperature overnight. To the reactionsolution was added water, the mixture was extracted with chloroform, andsodium sulfate was added to the combined extracts to dry them. Thesolvent was distilled off, and the resulting oil was subjected to silicagel column chromatography, and eluted with chloroform-methanol(100:0→94:6, v/v). Concentration of an objective fraction afforded acrude product (160 mg) of compound 576G.

MS: m/z=563 [M+H]⁺.

Seventh Step

To an EtOH (4 mL) solution of the crude product (160 mg) of compound576G obtained in the sixth step was added 2N NaOH (2 mL), and themixture was stirred at room temperature for 3 hours. To the reactionsolution was added a 2N aqueous HCl solution, the mixture was extractedwith ethyl acetate, and sodium sulfate was added to the combinedextracts to dry them. The solvent was distilled off, and the resultingoil was subjected to silica gel column chromatography, and eluted withchloroform-methanol (100:0→94:6, v/v). Concentration of an objectivefraction afforded 78 mg of compound 576H as a yellow solid.

MS: m/z=549 [M+H]⁺.

Eighth Step

To compound 576H (78 mg, 0.14 mmol) was added diphenyl ether (3 mL), andthe mixture was stirred at 245° C. for 1 hour under microwaveirradiation. The reaction solution was subjected to silica gel columnchromatography, and eluted with chloroform-methanol (100:0→90:10, v/v).Concentration of an objective fraction afforded 43 mg of compound 5761as a bronzed oil.

MS: m/z=505 [M+H]⁺.

Ninth Step

To compound 576I (42 mg, 0.083 mmol) was added TFA (1.0 mL), and themixture was stirred at room temperature for 35 minutes. The reactionsolution was subjected to toluene azeotropy, to the resultingconcentrated residue was added an aqueous saturated sodium bicarbonatesolution, and the mixture was extracted with ethyl acetate. To thecombined extracts was added sodium sulfate to dry them. The solvent wasdistilled off, to the resulting oil were added ethyl acetate andisopropyl ether, and the precipitated solid was filtered and washed toobtain 14 mg of compound 576 as a pale brown solid. ¹H-NMR (CDCl₃) δ:1.13 (3H, d, J=6.7 Hz), 1.20 (3H, d, J=6.7 Hz), 2.95-3.13 (2H, m), 3.28(1H, d, J=13.1 Hz), 3.37-3.59 (2H, m), 3.75 (1H, d, J=10.3 Hz), 4.10(1H, d, J=10.8 Hz), 4.80-4.87 (2H, m), 5.91 (1H, d, J=5.8 Hz), 6.41 (2H,t, J=6.5 Hz), 6.85 (1H, t, J=6.4 Hz), 7.05-7.35 (6H, m).

MS: m/z=415 [M+H]⁺.

Reference Example 577

First Step

To a dimethylformamide (3 mL) solution of a crude product (140 mg) ofcompound 159A was added potassium cyanide (21.0 mg, 0.323 mmol) at roomtemperature, and the mixture was stirred at 80° C. for 30 minutes, andat 100° C. for 30 minutes. The reaction solution was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/n-hexane=80%→100%) to obtaincompound 577B (41.5 mg, 33.5%) as a pale orange foam.

MS: m/z=535.25 [M+H]⁺.

Second Step

To an acetonitrile (4 mL) solution of compound 577B (41.5 mg, 0.078mmol) and sodium iodide (45.5 mg, 0.304 mmol) was addedchlorotrimethylsilane (0.0400 mL, 0.313 mmol) at room temperature, andthe mixture was stirred for 2 hours. To the reaction solution was addedwater (1 mL), the reaction solution was concentrated under reducedpressure, and the resulting residue was purified by preparative LCMS.Diethyl ether was added to the resulting residue to convert it into apowder, to obtain compound 577 (20.7 mg, 60.0%) as a gray white solid.

¹HNMR (DMSO-d₆) δ: 3.10 (3H, s), 3.51 (2H, m), 3.70 (1H, d, J=18.9 Hz),4.03 (1H, d, J=18.9 Hz), 4.46 (1H, d, J=13.4 Hz), 5.04 (1H, d, J=13.4Hz), 5.56 (1H, s), 5.69 (1H, s), 7.09-7.21 (5H, m), 7.39-7.63 (3H, m),7.64 (2H, m).

MS: m/z=445.20 [M+H]⁺.

Reference Example 578

Compound 578 was synthesized by the same procedure as that of Referenceexample 157.

¹HNMR (CDCl₃) δ: 0.97 (3H, d, J=6.6 Hz), 1.19 (3H, d, J=6.9 Hz), 3.29(3H, s), 3.97 (1H, d, J=16.1 Hz), 4.56 (1H, d, J=13.7 Hz), 4.82 (1H, m),4.96 (1H, d, J=16.1 Hz), 5.34 (1H, s), 5.97 (1H, d, J=13.7 Hz), 6.78(2H, m), 7.12 (2H, m), 7.44-7.51 (6H, m).

MS: m/z=434.10 [M+H]⁺.

Reference Example 579

Compound 579 was synthesized by the same procedure as that of Referenceexample 163.

MS: m/z=477.25 [M+H]⁺.

Reference Example 580

First Step

To a solution of compound 155A (10.5 g, 26.9 mmol),diisopropylethylamine (11.0 mL, 63.0 mmol), 1-methylimidazole (2.60 mL,32.6 mmol) and isopropylamine (2.80 mL, 32.7 mmol) in toluene (100 mL)and acetonitrile (20 mL) was added dropwise diphenylphosphoric acidchloride (6.80 mL, 32.7 mmol) over 5 minutes under ice-cooling, and themixture was stirred under ice-cooling for 90 minutes, at roomtemperature for 90 minutes. To the reaction solution were addedtert-butyldimethylsilyl chloride (4.05 g, 26.9 mmol) and triethylamine(4.10 mL, 29.6 mmol) under ice-cooling, the mixture was stirred at roomtemperature for 80 minutes, 4-dimethylaminopyridine (164 mg, 1.35 mmol)and methylene chloride (100 mL) were added at room temperature, and themixture was stirred for 15.5 hours. To the reaction solution was addedtert-butyldimethylsilyl chloride (2.04 g, 26.9 mmol) at roomtemperature, and the mixture was stirred for 24 hours. To the reactionsolution was added a 10% aqueous acetic acid solution (100 mL) at roomtemperature. The mixture was extracted with chloroform, the extractswere combined, washed with saturated sodium bicarbonate water (100 mL),and dried with sodium sulfate. The solvent was concentrated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/n-hexane=15%→40%) to obtaincompound 580B (6.96 g, 59.9%) as a pale yellow oil.

MS: m/z=432.25 [M+H]⁺.

Second Step

To an ethanol (50 mL) solution of compound 580B (6.96 g, 16.1 mmol) wasadded aqueous ammonia (35 mL) at room temperature, and the mixture wasstirred for 4 days. The reaction solution was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=75%→100%,methanol/chloroform=0%→15%) to obtain compound 580C (4.50 g, 64.8%) as apale orange gummy substance.

MS: m/z=431.25 [M+H]⁺.

Third Step

To a dimethylformamide (90 mL) solution of compound 580C (4.50 g, 10.5mmol) and potassium carbonate (7.27 g, 52.6 mmol) was addedO-(2,4-dinitrophenyl)hydroxylamine (6.29 g, 31.6 mmol) at roomtemperature, and the mixture was stirred for 2 days. To the reactionsolution was added chloroform (180 mL) at room temperature, theprecipitated insolubles were filtered off, the filtrate was concentratedunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (methanol/chloroform=0%→10%) to obtaincompound 580D (5.28 g, quant) as a yellow solid.

MS: m/z=446.25 [M+H]⁺.

Fourth Step

To an ethanol (15 ml) solution of compound 580D (1.29 g, 2.89 mmol) wasadded paraformaldehyde (261 mg, 8.68 mmol) at room temperature, and themixture was stirred at 140° C. for 3 hours under microwave irradiation.The reaction solution was concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography(ethyl acetate/n-hexane=50%→100%) to obtain compound 580E (2.47 g,93.0%) as a pale orange solid.

MS: m/z=458.20 [M+H]⁺.

Fifth Step

To a DMF (25 mL) solution of compound 580E (2.47 g, 5.40 mmol) wereadded cesium carbonate (5.28 g, 16.2 mmol) and bromodiphenylmethane(4.02 g, 16.3 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 2 days. To the reaction solution was added water(50 mL) under ice-cooling and, thereafter, the mixture was extractedwith ethyl acetate (150 mL×2). The extracts were combined, sequentiallywashed with water (50 mL×2) and an aqueous saturated sodium chloridesolution (50 mL), and dried with sodium sulfate. The solvent wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (ethylacetate/n-hexane=50%-100%, methanol/chloroform=10%→20%) to obtaincompound 580F (1.60 g, 47.5%) as a yellow form.

MS: m/z=624.30 [M+H]⁺.

Sixth Step

To a methanol (40 mL) solution of compound 580F (1.60 g, 2.56 mmol) wasadded hydrogen chloride (4N ethyl acetate solution, 20 mL) at roomtemperature, and the mixture was stirred for 2 hours. The reactionsolution was concentrated under reduced pressure, to the resultingresidue was added saturated sodium bicarbonate water (20 mL) at roomtemperature and, thereafter, the mixture was extracted with chloroformthree times. The extracts were combined, and dried with sodium sulfate,the solvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (ethyl acetate)to obtain compound 580G (920 mg, 70.4%) as a white foam.

MS: m/z=510.25 [M+H]⁺.

Seventh Step

To a THF (80 mL) solution of compound 580G (816 mg, 1.60 mmol) was addedmanganese dioxide (2.39 g, 27.5 mmol) at room temperature, and themixture was stirred for 19 hours. After the reaction solution wasfiltered, the filtrate was distilled off under reduced pressure, and theresulting crude product (785 mg) of compound 580H was used in a nextreaction without purification.

MS: m/z=508.20 [M+H]⁺.

Eighth Step

To a solution of the crude product (635 mg, 1.25 mmol) of compound 580Hobtained in the seventh step and amidosulfuric acid (425 mg, 4.38 mmol)in methanol (30 mL) and water (10 mL) was added dropwise a solution ofsodium chlorite (396 mg, 4.38 mmol) in water (4 mL) over 10 minutesunder ice-cooling, the mixture was stirred at room temperature for 30minutes, and a 5% aqueous sodium hydrogen sulfite solution (10 mL) wasadded. Methanol was distilled off under reduced pressure, and theresulting residue was extracted with ethyl acetate two times. Theextracts were combined, washed with an aqueous saturated sodium chloridesolution (10 mL), and dried with sodium sulfate. The filtrate wasdistilled off under reduced pressure, and the resulting crude product ofcompound 5801 was used in a next reaction without purification.

MS: m/z=524.25 [M+H]⁺.

Ninth Step

To a methylene chloride (20 mL) solution of the crude product (164 mg,0.313 mmol) of compound 580I obtained in the eighth step,diisopropylethylamine (0.131 mL, 0.751 mmol), 1-methylimidazole (0.0300mL, 0.376 mmol) and methylamine (2.0 M tetrahydrofuran solution, 0.188mL, 0.376 mmol) was added diphenylphosphoric acid chloride (0.0780 mL,0.375 mmol) at room temperature, the mixture was stirred for 3.5 hours,methylamine hydrochloride (25.0 mg, 0.370 mmol) was added, and themixture was stirred for 6 days. The reaction solution was distilled offunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (ethyl acetate/n-hexane=75%→100%) to obtaincompound 580J (45.7 mg, 27.2%) as a white foam.

MS: m/z=537.30 [M+H]⁺.

Tenth Step

To an acetonitrile (4 mL) solution of compound 580J (45.7 mg, 0.0850mmol) and sodium iodide (103 mg, 0.687 mmol) was addedchlorotrimethylsilane (0.0870 mL, 0.681 mmol) at room temperature, andthe mixture was stirred for 20 hours. To the reaction solution was addeda 5% aqueous sodium hydrogen sulfite solution (4 mL), and the mixturewas extracted with chloroform two times. After the extracts werecombined, and dried with sodium sulfate, the residue obtained byconcentration under reduced pressure was purified by preparative LCMS.Diethyl ether and n-hexane were added to the resulting residue toconvert it into a powder, to obtain compound 580 (17.1 mg, 45.0%) as awhite solid.

¹HNMR (CDCl₃) δ: 0.93 (3H, d, J=6.9 Hz), 1.11 (3H, d, J=6.9 Hz), 2.83(3H, d, J=4.8 Hz), 4.53 (1H, d, J=13.4 Hz), 4.85 (1H, m), 4.97 (1H, d,J=13.4 Hz), 5.07 (1H, brd), 5.25 (1H, s), 5.86 (1H, s), 6.97 (2H, m),7.15-7.24 (2H, m), 7.38-7.46 (6H, m).

MS: m/z=447.20 [M+H]⁺.

Reference Example 581

First Step

To a tert-butanol (4 mL) solution of compound 5801 (398 mg, 0.760 mmol)were added triethylamine (0.158 mL, 1.14 mmol) and diphenylphosphoricacid azide (0.196 mL, 0.912 mmol) at room temperature, and the mixturewas heated to reflux for 20 hours. To the reaction solution was addedwater (20 mL) at room temperature, and the mixture was extracted withchloroform three times. The extracts were combined, and dried withsodium sulfate. The solvent was distilled off under reduced pressure,and the resulting residue was purified by silica gel columnchromatography (methanol/chloroform=0%→10%) to obtain compound 581A (167mg, 36.9%) as a gray white solid.

MS: m/z=595.10 [M+H]⁺.

Second Step

To a methylene chloride (2 mL) solution of compound 581A (167 mg, 0.281mmol) was added trifluoroacetic acid (2 mL) at room temperature, and themixture was stirred for 1.5 hours. The reaction solution wasconcentrated under reduced pressure, and the resulting residue waspurified by preparative LCMS. Ethyl acetate, diethyl ether, and methanolwere added to the resulting residue to convert it into a powder, toobtain compound 581 (29.4 mg, 25.9%) as a white solid.

¹HNMR (DMSO-d₆) δ: 0.81 (3H, d, J=6.5 Hz), 0.98 (3H, d, J=6.5 Hz), 4.35(1H, d, J=12.6 Hz), 4.63 (1H, m), 4.68 (1H, d, J=12.6 Hz), 4.80 (1H, s),5.28 (1H, s), 6.34 (2H, s), 7.10-7.43 (8H, m), 7.81-7.83 (2H, m).

MS: m/z=404.95 [M+H]⁺.

Reference Example 582

First Step

To an ethanol (4 mL) solution of compound 582A (200 mg, 0.470 mmol)synthesized according to the synthesis method of Reference example 65was added paraformaldehyde (14.8 mg, 0.493 mmol) at room temperature,and the mixture was stirred at 140° C. for 45 minutes under microwaveirradiation. The reaction solution was distilled off under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=90%→100%) to obtain compound 582B(173 mg, 84.0%) as a white solid.

MS: m/z=438.15 [M+H]⁺.

Second Step

To a methylene chloride (4 mL) solution of compound 582B (173 mg, 0.396mmol), 4-dimethylaminopyridine (5.6 mg, 0.046 mmol) and triethylamine(0.164 mL, 1.18 mmol) was added 2-fluorobenzenesulfonyl chloride (0.0790mL, 0.597 mmol) at room temperature, and the mixture was stirred for 3days. The reaction solution was distilled off under reduced pressure,and the resulting residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=60%→80%) to obtain compound 582C(199 mg, 84.0%) as a white solid.

MS: m/z=596.15 [M+H]⁺.

Third Step

To an acetic acid (2 mL) solution of compound 582C (162 mg, 0.272 mmol)was added 48% aqueous hydrogen bromide (2 mL) at room temperature, andthe mixture was stirred at 100° C. for 20 minutes under microwaveirradiation. The solvent was distilled off under reduced pressure, anddiethyl ether and methanol were added to the resulting residue toconvert it into a powder, to obtain compound 582 (160 mg, quant) as ayellow solid.

-   -   ¹HNMR (DMSO-d₆) δ: 4.34 (1H, d, J=14.7 Hz), 4.59 (1H, d, J=14.7        Hz), 5.50 (1H, d, J=14.3 Hz), 5.81 (1H, d, J=14.3 Hz), 7.15-7.21        (2H, m), 7.35-7.40 (2H, m), 7.45-7.61 (2H, m), 7.78 (1H, m),        7.93 (1H, m), 8.42 (1H, s).

MS: m/z=492.10 [M+H]⁺.

Reference Example 583, Reference Example 584

First Step

Compound 583A (3.0 g, 0.99 mmol) synthesized according to Referenceexample 95 was added to toluene (300 ml) and acetic acid (30.0 ml) todissolve, and TsOH H2O (0.1 g, 0.526 mmol) was added at roomtemperature. The reaction mixture was stirred for 3 hours underheat-refluxing. After concentration under reduced pressure, the residuewas purified by amino silica gel column chromatography (CHCl3/MeOH 50:1)to obtain compound 583B (1.8 g, 72.4%).

MS: m/z=312 [M+H]⁺.

Second Step

Compound 583B (233 mg, 0.748 mmol) and compound 403C (197 mg, 0.8 mmol)were suspended in THF (7.5 ml), and NaHMDS (1.123 ml, 1.123 mmol, 1M-THFsolution) was added at room temperature under nitrogen stream. Afterstirring at room temperature for 3 hours, water was added, and themixture was extracted with ethyl acetate (2×30 mL). The ethyl acetatelayer was washed with an aqueous saturated sodium chloride solution, anddried with sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (CHC3/MeOH 20:1) to obtain compound 583D (90 mg, 23.1%).

MS: m/z=522 [M+H]⁺.

Third Step

Compound 583D (90 mg, 0.173 mmol) was dissolved in a mixed solvent ofMeOH (3 ml) and THF (3.00 ml), and 10% palladium-carbon (90 mg, 0.846mmol) was added. The mixture was stirred for 24 hours under hydrogen (2atm) stream, and insolubles were filtered. The residue was purifiedusing HPLC (MeCN—H2O), and diastereomers were resolved.

First Fraction (Compound 583)

(15 mg, 20.1%)

MS: m/z=432 [M+H]⁺.

Second Fraction (Compound 584)

(45 mg, 60.4%)

MS: m/z=432 [M+H]⁺.

Reference Example 585

Compound 585 was synthesized by the same procedure as that of Referenceexample 403.

¹H-NMR (DMSO-d₆) δ: 1.87-2.28 (4H, m), 3.40-3.80 (3H, m), 4.32 (1H, d,J=12.96 Hz), 5.34 (1H, t, J=7.32 Hz), 5.65 (1H, d, J=7.63 Hz), 6.90 (1H,d, J=7.78 Hz), 7.10-7.35 (5H, m).

MS: m/z=312 [M+H]⁺.

Reference Example 586

First Step

Compound 95B (2.29 g, 8.12 mmol) was dissolved in pyridine (10 ml),iso-propyl-D₇-amine hydrochloride (1.00 g, 9.75 mmol),1H-benzo[d][1,2,3]triazol-1-ol (1.10 g, 8.12 mmol) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (3.11 g, 16.2 mmol) were added, and the mixture wasstirred at room temperature for 20 hours. The reaction solution waspoured into water, the mixture was extracted with ethyl acetate, and theextract was dried with sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting crude product was purified bysilica gel column chromatography, and eluted with chloroform-methanol(97:3, v/v). To the resulting compound was added diethyl ether, and theprecipitated residue was filtered to obtain 1.36 g of a white solid586B.

Second Step

Compound 586B (1.36 g, 4.64 mmol) obtained in the first step wasdissolved in dimethylformamide (20 ml), potassium carbonate (3.20 g,23.2 mmol) was added, and the mixture was stirred at room temperaturefor 50 minutes. O-(2,4-dinitrophenyl)hydroxylamine (1.85 g, 9.27 mmol)was added, and the mixture was stirred at room temperature for 18 hours.To the reaction solution was added chloroform, the generated precipitatewas removed by filtration, and the filtrate was concentrated underreduced pressure. The resulting crude product was purified by aminocolumn chromatography, and eluted with chloroform-methanol (97:3, v/v)to obtain 835 mg of a colorless solid 586C.

¹H-NMR (CDCl₃) δ: 5.28 (2H, s), 5.63 (2H, s), 6.32 (1H, d, J=7.7 Hz),7.10 (1H, brs), 7.42 (6H, m).

Third Step

Compound 586C (581 mg, 1.88 mmol) obtained in the second step andparaformaldehyde-D₂ (181 mg, 5.65 mmol) were added to ethanol (12 ml),and the mixture was stirred at 140° C. for 30 minutes under microwaveirradiation. The reaction solution was concentrated under reducedpressure, and the resulting crude product was purified by amino columnchromatography, and eluted with chloroform-methanol (97:3, v/v). To theresulting compound was added diethyl ether, and the precipitated residuewas filtered to obtain 140 mg of white solid 586D.

¹H-NMR (CDCl₃) δ: 4.39 (2H, d, J=8.1 Hz), 5.36 (2H, s), 5.42 (1H, t,J=8.0 Hz), 6.37 (1H, d, J=7.6 Hz), 7.48 (6H, m).

Fourth Step

Compound 586E (972 mg, 5.78 mmol) was dissolved in tetrahydrofuran (10ml), sodium hydride (60%, 231 mg, 5.78 mmol) and benzyl bromide-D₂ (1.00g, 5.78 mmol) were added at 0° C., and the mixture was stirred at 60° C.for 30 minutes. The reaction solution was added to dilute hydrochloricacid, the mixture was extracted with ethyl acetate, and the organiclayer was washed with an aqueous sodium bicarbonate solution. Thesolvent was distilled off under reduced pressure to obtain 1.48 g of awhite solid 586F.

¹H-NMR (CDCl₃) δ: 3.95 (3H, s), 7.17-7.48 (8H, m), 8.00 (1H, dd, J=7.8,1.3 Hz).

Fifth Step

Compound 586F (1.50 g, 5.76 mmol) obtained in the fourth step wasdissolved in methanol (20 ml) and tetrahydrofuran (20 ml), a 2N aqueoussodium hydroxide solution (14.4 ml, 28.8 mmol) was added, and themixture was stirred at room temperature for 3 hours. To the reactionsolution was added dilute hydrochloric acid to make the solution acidic,the mixture was extracted with ethyl acetate, and the organic layer waswashed with an aqueous saturated sodium chloride solution, and driedwith sodium sulfate. The solvent was distilled off under reducedpressure, to the resulting compound were added n-hexane-ethyl acetate,and the precipitated residue was filtered to obtain 1.17 g of a whitesolid 586G.

¹H-NMR (CDCl₃) δ: 7.18-7.48 (8H, m), 8.11 (1H, dd, J=7.9, 1.6 Hz).

Sixth Step

To compound 586G (1.15 g, 4.67 mmol) obtained in the fifth step wasadded toluene (10 ml), dimethylformamide (0.100 ml, 1.29 mmol) andthionyl chloride (0.410 ml, 5.60 mmol) were added, and the mixture wasstirred at 130° C. for 1.5 hours. After cooled to room temperature, thereaction solution was concentrated under reduced pressure. To theresulting compound was added n-hexane, and the precipitated residue wasfiltered to obtain 1.16 g of a white solid. To aluminum chloride (718mg, 5.38 mmol) were added dichloromethane (10 ml) and nitromethane (0.5ml), a dichloromethane solution (5 ml) of 500 mg of the compoundobtained above was added at 0° C., and the mixture was stirred at roomtemperature for 5 hours. To the reaction solution was added an aqueoussodium hydroxide solution, the mixture was extracted with methylenechloride, and the organic layer was dried with sodium sulfate. Thesolvent was concentrated under reduced pressure, and the resulting crudeproduct was purified by silica gel column chromatography, and elutedwith n-hexane-ethyl acetate (4:1, v/v). To the resulting compound wasadded n-hexane, and the precipitated residue was filtered to obtain 155mg of a pale yellow solid 586H.

¹H-NMR (CDCl₃) δ: 7.21-7.39 (6H, m), 7.46 (1H, td, J=7.5, 1.4 Hz), 7.59(1H, dd, J=7.5, 1.4 Hz), 8.21 (1H, dd, J=8.0, 1.0 Hz).

Seventh Step

Compound 586H (150 mg, 0.657 mmol) obtained in the sixth step wasdissolved in tetrahydrofuran (3 ml), lithium aluminum hydride-D₄ (13.8mg, 0.329 mmol) was added at 0° C., and the mixture was stirred at roomtemperature for 2 hours. To the reaction solution was added dilutehydrochloric acid, the mixture was extracted with ethyl acetate, anddried with sodium sulfate, and the solvent was distilled off underreduced pressure. To the resulting compound were addedn-hexane-dichloromethane, and the precipitated residue was filtered toobtain 114 mg of a white solid 5861.

¹H-NMR (CDCl₃) δ: 7.17 (6H, m), 7.40-7.52 (2H, m).

Eighth Step

Compound 586D (76.0 mg, 0.236 mmol) and 5861 (54.5 mg, 0.236 mmmol) weredissolved in acetic acid (3.2 ml), and concentrated sulfuric acid (0.8ml) was added dropwise under water-cooling. After the mixture wasstirred at room temperature for 30 minutes, the mixture was poured intowater, and extracted with ethyl acetate. The organic layer was driedwith sodium sulfate, the solvent was distilled off under reducedpressure, to the resulting crude product were added ethylacetate-diethyl ether, and the precipitated residue was filtered toobtain 32 mg of a white solid 586.

¹H-NMR (DMSO-d₆) δ: 5.57 (1H, d, J=7.3 Hz), 6.82-7.44 (9H, m).

MS: m/z=446 [M+H]⁺

Using a commercially available heavy hydrogen reagent, and according toReference example 586, compounds 587 to 591 were synthesized.

Reference Example 587

MS: m/z=436 [M+H]⁺

Reference Example 588

¹H-NMR (DMSO-d₆) δ: 3.87 (1H, d, J=13.4 Hz), 5.58 (1H, d, J=7.8 Hz),5.60 (1H, d, J=12.6 Hz), 6.81-7.48 (9H, m).

Reference Example 589

MS: m/z=441 [M+H]⁺

Reference Example 590

MS: m/z=435 [M+H]⁺

Reference Example 591

MS: m/z=436 [M+H]⁺

Reference Example 592

First Step

Compound 592A (22.8 g, 64.1 mmol) and7-(trifluoromethyl)-6,11-dihydrodibenzo[b,e]thiepin-11-ol (19 g, 64.1mmol) were suspended in 1,2-dichloroethane, dichloroacetic acid (13.2mL, 160 mmol) was added, and the mixture was stirred for 2.5 hours underheat-refluxing. The mixture was cooled to room temperature and dilutedwith dichloromethane, then washed with an aqueous saturated sodiumbicarbonate solution and an aqueous saturated sodium chloride solution,and dried. The solvent was distilled off, and the resulting solid wassolidified by adding ethyl acetate-diisopropylether to obtain 32 g(containing 10% of 592A) of compound 592B.

MS: m/z=634 [M+H]⁺.

Rf: 0.56 (AcOEt only).

Second Step

To an N,N-dimethylacetoamide (120 mL) solution of compound 592B (6.0 g,9.47 mmol) were added2-tert-butylimino2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine(16.5 mL, 56.8 mmol) and paraformaldehyde (569 mg, 18.9 mmol), and themixture was stirred at room temperature for 3 hours. Subsequently, TsCl(3.61 g, 18.9 mmol) was slowly added, and the mixture was stirred forfurther 2 hours. To the reaction solution was added a 1N aqueous HClsolution, and the mixture was extracted with ethyl acetate two times.The organic layer was washed with water and an aqueous saturated sodiumchloride solution, and dried. After the solvent was distilled off, theresulting solid was purified by silica gel column chromatography. Thematerials were eluted firstly with hexane-ethyl acetate (2:3, v/v) and,then eluted with hexane-ethyl acetate (1:9, v/v). Concentration of anobjective fraction afforded 1.74 g of compound 592C as a pale yellowsolid.

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=7.2 Hz), 3.96 (1H, d, J=14.6 Hz), 4.34(1H, d, J=13.2 Hz), 4.81 (1H, d, J=13.2 Hz), 5.17 (1H, s), 5.46 (1H, d,J=10.8 Hz), 5.56 (1H, d, J=10.8 Hz), 5.60 (1H, m), 5.82 (1H, d, J=14.6Hz), 5.87 (1H, d, J=7.7 Hz), 6.56 (1H, d, J=7.2 Hz), 6.73 (1H, m),7.04-7.11 (2H, m), 7.09 (1H, d, J=7.7 Hz), 7.29-7.38 (5H, m), 7.56 (2H,m), 7.78 (1H, m).

MS: m/z=646 [M+H]⁺.

Rf: 0.65 (AcOEt only).

Third Step

To an N,N-dimethylacetoamide (34 mL) solution of compound 592C (1.7 g,2.63 mmol) were added anhydrous LiCl (1.3 g, 31.6 mmol) andparaformaldehyde (569 mg, 18.9 mmol), and the mixture was stirred at100° C. for 3 hours. To the reaction solution was added a 1N aqueous HClsolution, and the mixture was extracted with ethyl acetate two times.The organic layer was washed with water and an aqueous saturated sodiumchloride solution, and dried. After the solvent was distilled off, theresulting solid was purified by silica gel column chromatography. Thematerials were eluted firstly with chloroform-methanol (99:1, v/v) and,then, with chloroform-methanol (96:4, v/v). An objective fraction wasconcentrated, and the resulting solid was solidified by adding ethylacetate-diisopropylether to obtain 1.33 g of compound 592 as a colorlesssolid.

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.2 Hz), 2.90 (1H, brs), 3.99 (1H, d,J=14.5 Hz), 4.45 (1H, d, J=13.2 Hz), 4.92 (1H, d, J=13.2 Hz), 5.24 (1H,s), 5.54 (1H, m), 5.83 (1H, d, J=7.72 Hz), 5.87 (1H, d, J=14.5 Hz), 6.70(1H, d, J=7.1 Hz), 6.84 (1H, m), 7.07-7.16 (2H, m), 7.13 (1H, d, J=7.7Hz), 7.36-7.42 (2H, m), 7.80 (1H, m).

MS: m/z=556 [M+H]⁺.

Rf: 0.46 (CHCl3: MeOH=9:1).

Reference Example 593

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.0 Hz), 4.12 (1H, d, J=13.7 Hz),4.49 (1H, d, J=13.1 Hz), 5.14 (1H, d, J=13.0 Hz), 5.20 (1H, m), 5.68(3H, m), 6.74 (1H, d, J=7.5 Hz), 6.93 (1H, m), 7.12-7.46 (5H, m).

Reference Example 594

¹H-NMR (DMSO-d₆) δ: 1.21 (3H, d, J=7.2 Hz), 4.27 (1H, d, J=14.1 Hz),4.61 (1H, d, J=13.4 Hz), 5.08 (1H, d, J=13.4 Hz), 5.47 (1H, m), 5.55(1H, d, J=15.8 Hz), 5.75 (1H, d, J=7.6 Hz), 5.83 (1H, s), 6.97 (1H, t,J=7.8 Hz), 7.06 (1H, dd, J=7.8, 1.6 Hz), 7.21 (1H, d, J=7.7 Hz), 7.41(4H, m).

MS: m/z=540 [M+H]⁺.

Reference Example 595

¹H-NMR (DMSO-d₆) δ: 1.42 (3H, d, J=7.2 Hz), 4.08 (1H, d, J=13.3 Hz),4.49 (1H, d, J=13.1 Hz), 5.12 (1H, m), 5.16 (1H, d, J=13.1 Hz), 5.51(1H, s), 5.70 (2H, m), 6.93 (1H, t, J=7.8 Hz), 7.05 (1H, dd, J=7.9, 1.3Hz), 7.18 (2H, m), 7.37-7.43 (3H, m).

MS: m/z=540 [M+H]⁺.

Reference Example 596

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.2 Hz), 3.90 (1H, d, J=12.8 Hz),4.42 (1H, d, J=13.1 Hz), 5.12 (1H, m), 5.14 (1H, d, J=12.5 Hz), 5.36(1H, s), 5.58 (1H, d, J=13.4 Hz), 5.71 (1H, d, J=7.5 Hz), 6.70 (1H, td,J=8.3, 2.6 Hz), 6.96-7.06 (2H, m), 7.21 (1H, d, J=7.6 Hz), 7.26 (2H, d,J=3.5 Hz), 7.42 (2H, m).

MS: m/z=506 [M+H]⁺.

Reference Example 597

¹H-NMR (DMSO-d₆) δ: 1.38 (3H, d, J=7.2 Hz), 4.23 (1H, d, J=13.9 Hz),4.52 (1H, d, J=13.1 Hz), 5.10 (1H, m), 5.12 (1H, d, J=12.8 Hz), 5.44(1H, d, J=14.2 Hz), 5.52 (1H, s), 5.69 (1H, d, J=7.6 Hz), 6.91 (1H, t,J=7.8 Hz), 7.04 (1H, d, J=7.2 Hz), 7.15 (2H, m), 7.28-7.40 (3H, m).

MS: m/z=540 [M+H]⁺.

Reference Example 598

¹H-NMR (DMSO-d₆) δ: 1.12 (3H, d, J=7.3 Hz), 4.02 (1H, d, J=13.1 Hz),4.50 (1H, d, J=13.4 Hz), 5.07 (1H, d, J=13.4 Hz), 5.50 (1H, m), 5.64(1H, d, J=13.4 Hz), 5.69 (1H, s), 5.75 (1H, d, J=7.5 Hz), 6.73 (1H, td,J=8.5, 2.6 Hz), 7.02 (2H, m), 7.21 (2H, m), 7.35 (1H, d, J=7.0 Hz), 7.47(1H, t, J=6.8 Hz).

MS: m/z=524 [M+H]⁺.

Reference Example 599

¹H-NMR (DMSO-d₆) δ: 1.10 (3H, d, J=7.5 Hz), 4.11 (1H, d, J=13.6 Hz),4.51 (1H, d, J=13.4 Hz), 5.05 (1H, d, J=13.3 Hz), 5.49 (1H, m), 5.67(3H, m), 6.80 (1H, d, J=7.8 Hz), 6.92 (1H, dd, J=13.6, 7.7 Hz),7.11-7.24 (3H, m), 7.36 (1H, d, J=7.5 Hz), 7.47 (1H, t, J=6.9 Hz).

MS: m/z=524 [M+H]⁺.

Reference Example 600

¹H-NMR (DMSO-d₆) δ: 1.19 (3H, d, J=7.2 Hz), 3.86 (3H, s), 4.22 (1H, d,J=13.3 Hz), 4.49 (1H, d, J=13.1 Hz), 5.06 (1H, d, J=13.3 Hz), 5.34 (1H,d, J=13.3 Hz), 5.46 (1H, m), 5.55 (1H, s), 5.65 (1H, d, J=7.8 Hz), 6.84(1H, t, J=7.2 Hz), 6.94 (1H, d, J=7.8 Hz), 7.14 (6H, m).

MS: m/z=518 [M+H]⁺.

Reference Example 601

¹H-NMR (DMSO-d₆) δ: 1.09 (3H, d, J=7.1 Hz), 4.15 (1H, d, J=13.6 Hz),4.53 (1H, d, J=13.6 Hz), 5.07 (1H, d, J=14.0 Hz), 5.48 (1H, m), 5.70(3H, m), 6.93 (2H, m), 7.14-7.26 (2H, m), 7.35-7.51 (3H, m).

MS: m/z=540 [M+H]⁺.

Reference Example 602

¹H-NMR (DMSO-d₆) δ: 1.18 (3H, d, J=7.0 Hz), 4.03 (1H, d, J=14.5 Hz),4.47 (1H, d, J=13.6 Hz), 5.03 (1H, d, J=13.1 Hz), 5.46 (1H, m),5.68-5.74 (3H, m), 6.94 (2H, m), 7.10-7.17 (2H, m), 7.34-7.40 (2H, m),7.63 (1H, m).

MS: m/z=540 [M+H]⁺.

Reference Example 603

¹H-NMR (DMSO-d₆) δ: 1.14 (3H, t, J=6.3 Hz), 3.90 (1H, d, J=13.6 Hz),4.39 (1H, d, J=13.4 Hz), 5.06 (1H, d, J=13.0 Hz), 5.46 (1H, m), 5.63(1H, s), 5.64 (1H, d, J=13.2 Hz), 5.73 (1H, d, J=7.6 Hz), 6.73 (1H, td,J=8.3, 2.7 Hz), 6.96-7.04 (2H, m), 7.21 (1H, d, J=7.6 Hz), 7.27 (1H, dt,J=10.3, 3.7 Hz), 7.43 (2H, m), 7.53 (1H, d, J=7.3 Hz).

MS: m/z=506 [M+H]⁺.

Reference Example 604

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.2 Hz), 4.01 (1H, d, J=13.4 Hz),4.47 (1H, d, J=13.1 Hz), 5.17 (1H, d, J=12.7 Hz), 5.20 (1H, m), 5.63(1H, d, J=13.7 Hz), 5.66 (1H, s), 5.72 (1H, d, J=7.6 Hz), 6.72 (1H, td,J=8.3, 2.8 Hz), 6.92 (1H, dd, J=8.6, 6.0 Hz), 7.04 (1H, dd, J=10.0, 2.5Hz), 7.19 (2H, m), 7.30 (1H, d, J=7.0 Hz), 7.43 (1H, m).

MS: m/z=524 [M+H]⁺.

Reference Example 605

¹H-NMR (DMSO-d₆) δ: 1.37 (3H, d, J=7.3 Hz), 3.85 (3H, s), 4.23 (1H, d,J=13.6 Hz), 4.50 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 5.14 (1H,m), 5.28 (1H, s), 5.30 (1H, d, J=12.4 Hz), 5.63 (1H, d, J=7.8 Hz),6.80-7.25 (8H, m).

MS: m/z=518 [M+H]⁺.

Reference Example 606

¹H-NMR (DMSO-d₆) δ: 1.35 (3H, d, J=7.5 Hz), 4.13 (1H, d, J=13.9 Hz),4.48 (1H, d, J=13.1 Hz), 5.14 (1H, d, J=12.5 Hz), 5.20 (1H, m), 5.69(3H, m), 6.90 (2H, m), 7.18 (2H, m), 7.32 (1H, d, J=8.1 Hz), 7.43 (2H,m).

MS: m/z=540 [M+H]⁺.

Reference Example 607

MS: m/z=524 [M+H]⁺.

Reference Example 608

MS: m/z=524 [M+H]⁺.

Reference Example 609

MS: m/z=448 [M+H]⁺. RT=1.54 min.

Reference Example 610

MS: m/z=522 [M+H]⁺. RT=1.84 min.

Reference Example 611

MS: m/z=522 [M+H]⁺. RT=1.76 min.

Reference Example 612

MS: m/z=536 [M+H]⁺

Reference Example 613

MS: m/z=516 [M+H]⁺

Reference Example 614

MS: m/z=520 [M+H]⁺

Reference Example 615

MS: m/z=536 [M+H]⁺

Reference Example 616

MS: m/z=516 [M+H]⁺

Reference Example 617

MS: m/z=520 [M+H]⁺

Reference Example 618

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=7.5 Hz), 3.82 (1H, d, J=13.7 Hz), 4.49(1H, d, J=13.1 Hz), 4.91 (1H, d, J=13.7 Hz), 5.18 (1H, s), 5.51 (1H, m),5.71 (1H, d, J=13.1 Hz), 5.88 (1H, d, J=7.5 Hz), 6.94 (2H, m), 7.14-7.52(6H, m).

MS: m/z=513.20 [M+H]⁺.

Reference Example 619

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=7.3 Hz), 2.00 (1H, brs), 3.65 (1H, d,J=13.6 Hz), 4.46 (1H, d, J=13.3 Hz), 4.87 (1H, d, J=13.3 Hz), 5.17 (1H,s), 5.51 (1H, m), 5.74 (1H, d, J=13.6 Hz), 5.86 (1H, d, J=7.7 Hz),6.68-6.75 (2H, m), 6.98 (1H, dt, J=2.6, 8.3 Hz), 7.10 (1H, d, J=7.7 Hz),7.11 (1H, dd, J=2.6, 8.3 Hz), 7.17 (1H, dd, J=5.3, 8.3 Hz), 7.45 (1H,dd, J=2.6, 6.9 Hz).

MS: m/z=585 [M+H]⁺.

Reference Example 620

¹H-NMR (CDCl₃) δ: 1.42 (3H, d, J=7.3 Hz), 2.00 (1H, brs), 3.63 (1H, d,J=13.6 Hz), 4.54 (1H, d, J=12.6 Hz), 5.05 (1H, d, J=12.6 Hz), 5.24 (1H,s), 5.37 (1H, m), 5.77 (1H, d, J=13.6 Hz), 5.79 (1H, d, J=7.6 Hz), 6.68(1H, d, J=7.3 Hz), 6.73 (1H, dd, J=2.1, 7.3 Hz), 6.97 (1H, dt, J=2.6,8.4 Hz), 7.04 (1H, dd, J=2.6, 8.4 Hz), 7.16 (1H, d, J=7.6 Hz), 7.16 (1H,m), 7.42 (1H, dd, J=2.1, 7.3 Hz).

MS: m/z=585 [M+H]⁺.

Reference Example 621

MS: m/z=540 [M+H]⁺.

Reference Example 622

MS: m/z=540 [M+H]⁺.

Reference Example 623

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=7.3 Hz), 2.10 (1H, brs), 2.25 (3H, s),4.21 (1H, d, J=13.6 Hz), 4.48 (1H, d, 13.3 Hz), 4.89 (1H, d, J=13.3 Hz),5.18 (1H, s), 5.37 (1H, dd, J=2.0, 13.6 Hz), 5.52 (1H, s), 5.80 (1H, d,J=7.8 Hz), 6.57 (1H, d, J=7.2 Hz), 6.75 (1H, t, J=7.6 Hz), 6.97-7.04(2H, m), 7.12 (1H, d, J=7.8 Hz), 7.17-7.24 (2H, m).

MS: m/z=520 [M+H]⁺.

Reference Example 624

First Step

Compound 624A (14.7 g, 87.0 mmol) and methyl 2-(bromomethyl)benzoate(20.0 g, 87.0 mmol) were dissolved in DMF (200 ml), cesium carbonate(42.7 g, 131 mmol) was added, and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was filtered, ethylacetate was added to the filtrate, and the mixture was washed with waterand an aqueous saturated sodium bicarbonate solution. After the organiclayer was dried with sodium sulfate, the solvent was distilled off underreduced pressure. The resulting solid was crushed by adding hexane, andfiltered out to obtain 26.2 g of a white solid 624B.

¹H-NMR (CDCl₃) δ: 3.89 (6H, s), 4.64 (2H, s), 7.14-7.52 (6H, m), 7.94(2H, t, J=7.1 Hz).

Second Step

Compound 624B (26.2 g, 83.0 mmol) was dissolved in methanol (200 ml) andTHF (200 ml), a 2N aqueous sodium hydroxide solution (207 ml, 414 mmol)was added at room temperature, and the mixture was stirred at roomtemperature for 3 days. To the reaction solution was added dilutehydrochloric acid to make the solution acidic, and the generated whiteprecipitate was filtered and dried to obtain 23.1 g of a white solid624C.

¹H-NMR (DMSO-d₆) δ: 4.58 (2H, s), 7.20 (1H, td, J=7.2, 1.3 Hz),7.35-7.54 (5H, m), 7.85 (2H, t, J=6.9 Hz).

Third Step

To compound 624C (2.66 g, 9.23 mmol) was added polyphosphoric acid (30g), and the mixture was stirred at 120° C. for 3 hours. After thereaction solution was cooled to room temperature, water was added, themixture was extracted with ethyl acetate, and the organic layer wasdried with sodium sulfate. The solvent was distilled off under reducedpressure to obtain 2.37 g of a pale brown solid 624D.

¹H-NMR (CDCl₃) δ: 4.05 (2H, s), 7.27 (1H, d, J=7.4 Hz), 7.36-7.42 (2H,m), 7.52 (1H, td, J=7.6, 1.3 Hz), 7.62 (1H, dd, J=7.5, 1.1 Hz), 8.23(1H, dd, J=7.6, 1.7 Hz), 8.52 (1H, dd, J=8.1, 1.7 Hz).

Fourth Step

To compound 624D (96.0 mg, 0.355 mmol) was added toluene (2 ml), DMF(0.028 mmol) and thionyl chloride (0.131m, 1.80 mmol) were added, andthe mixture was stirred at 130° C. for 1 hour. After the solvent wasdistilled off under reduced pressure, the substance was dissolved inmethanol (1 ml) and THF (1 ml), sodium borohydride (100 mg, 2.64 mmol)was added, and the mixture was stirred at room temperature for 1 hour.To the reaction solution was added an aqueous ammonium chloridesolution, the mixture was extracted with ethyl acetate, and the organiclayer was dried with sodium sulfate. The solvent was distilled off underreduced pressure, and the resulting crude product was purified by silicagel column chromatography and eluted with n-hexane-ethyl acetate (1:1,v/v) to obtain 41 mg of a white solid 624E.

¹H-NMR (CDCl₃) δ: 2.09 (1H, t, J=6.3 Hz), 2.79 (1H, d, J=3.7 Hz), 4.43(2H, d, J=1.3 Hz), 4.76 (2H, m), 6.33 (1H, d, J=3.0 Hz), 7.18-7.34 (5H,m), 7.52-7.56 (2H, m).

Fifth Step

Compound 624E (40.0 mg, 0.155 mmol) was dissolved in dichloromethane (2ml), pyridine (61.2 mg, 0.774 mmol) and benzoyl chloride (21.8 mg, 0.155mmol) were added, and the mixture was stirred at room temperature for 2hours. To the reaction solution was added water, the mixture wasextracted with ethyl acetate, and the organic layer was dried withsodium sulfate. The solvent was distilled off under reduced pressure,and the resulting crude product was purified by silica gel columnchromatography and eluted with n-hexane-ethyl acetate (1:1, v/v) toobtain 30 mg of a white solid 624F.

¹H-NMR (CDCl₃) δ: 2.83 (1H, d, J=3.4 Hz), 4.27 (1H, d, J=13.9 Hz), 4.41(1H, d, J=14.0 Hz), 5.42 (2H, s), 6.35 (1H, d, J=2.9 Hz), 7.12-7.58 (5H,m), 8.06 (2H, dd, J=8.2, 1.4 Hz).

Hereinbelow, according to Reference example 592, compound 624 wassynthesized by the same procedure.

MS: m/z=518 [M+H]⁺.

Reference Example 625

First Step

To a toluene (3.3 ml) solution of compound 625A (700 mg, 2.29 mmol) wereadded 2-pyrrolidone (264 μL, 3.44 mmol), N,N′-dimethylethylene diamine(49 μL, 0.46 mmol), copper iodide (87 mg, 0.46 mmol), and potassiumcarbonate (634 mg, 4.59 mmol) under nitrogen stream, and the mixture wasstirred at 110° C. for 8 hours. After cooled to room temperature, thereaction solution was directly purified by silica gel columnchromatography. Elution with chloroform-methanol (19:1, v/v) andconcentration of an objective fraction afforded 620 mg of compound 625Bas a gray white solid.

MS: m/z=310 [M+H]⁺.

Rf: 0.50 (CHCl3: MeOH=19:1).

Second Step

A THF (8 mL) solution of compound 625B (620 mg, 2.0 mmol) was added toan ice-cooled MeOH (4 ml) solution of NaBH4 (227 mg, 6.0 mmol), and themixture was stirred for 1 hour. After water was added, followed byextraction with ethyl acetate two times, the organic layer was washedwith an aqueous saturated sodium chloride solution, and dried. Thesolvent was distilled off, and the resulting solid was purified bysilica gel column chromatography. Elution with chloroform-methanol(19:1, v/v) and concentration of an objective fraction afforded 621 mgof compound 625C as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.26 (2H, m, J=6.9, 7.2, 8.0 Hz), 2.61 (2H, t, J=8.0Hz), 2.89 (1H, d, J=2.9 Hz), 3.77 (2H, m, J=6.9, 7.2, 9.7 Hz), 4.24 (1H,brs), 6.13 (1H, s), 7.02-7.14 (4H, m), 7.29 (1H, t, J=7.8 Hz), 7.46 (1H,d, J=7.2 Hz), 7.56 (1H, d, J=6.0 Hz).

Rf: 0.30 (CHCl3: MeOH=19:1).

Hereinbelow, according to Reference example 592, compound 625 wassynthesized by the same procedure.

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.32), 2.33 (2H, m), 2.65 (2H, t, J=8.1Hz), 3.65 (1H, d, J=14.2 Hz), 3.77-3.95 (2H, m), 4.60 (1H, d, J=13.4Hz), 4.87 (1H, d, J=13.4 Hz), 5.16 (1H, s), 5.48 (1H, m), 5.50 (1H, d,J=14.2 Hz), 5.82 (1H, d, J=7.7 Hz), 6.70 (1H, dd, J=1.2, 7.6 Hz), 6.83(1H, dt, J=7.6, 10.2 Hz), 7.04-7.17 (4H, m), 7.13 (1H, d, J=7.7 Hz),7.31 (1H, d, J=5.3 Hz), 7.31 (1H, d, J=3.7 Hz).

MS: m/z=571 [M+H]⁺.

Reference Example 626

First Step

A N,N-dimethylformamide (200 mL) solution of compound 626A (20.0 g, 114mmol) and phenylmethanethiol (14.19 g, 114 mmol) was cooled to 1 to 3C,and t-butoxypotassium (14.11 g, 126 mmol) was put over 20 minutes whilethe same temperature was retained. After the reaction solution wasstirred at the same temperature for 30 minutes, temperature wasgradually raised to room temperature, and the mixture was stirred at thesame temperature for 2 hours. Ice water was added, and the mixture wasextracted with ethyl acetate. The extract was washed with water threetimes, washed with an aqueous saturated sodium chloride solution, anddried. The solvent was distilled off, and the resulting oil wassolidified by adding diisopropyl ether to obtain 15.0 g of compound626B.

¹H-NMR (CDCl₃) δ: 4.16 (2H, s), 7.19-7.41 (8H, m), 10.61 (1H, s).

MS: m/z=263 [M+H]⁺.

Second Step

Compound 626B (6.9 g, 26.3 mmol) was suspended in 1,4-dioxane (60 mL),SULFAMIC ACID (5.61 g, 57.8 mmol) was added, and the mixture was cooledto I to 3° C. To the reaction solution was added dropwise an aqueoussolution (20 ml) of sodium hypochlorite (5.23 g, 57.8 mmol) over 10minutes while temperature was retained at the same temperature. Afterthe reaction solution was stirred at the same temperature for 30minutes, temperature was gradually raised to room temperature, and themixture was stirred at the same temperature for 2 hours. To the reactionsolution was added ice water, and the mixture was extracted with ethylacetate. The extract was washed with an aqueous saturated sodiumchloride solution, and dried. The solvent was distilled off, and theresulting oil was solidified by adding diisopropyl ether to obtain 7.1 gof compound 626C.

¹H-NMR (DMSO-d6) δ: 3.99 (1H, d, J=11.2 Hz), 4.41 (1H, d, J=11.2 Hz),7.11 (2H, brs), 7.33 (3H, brs), 7.49 (1H, d, J=7.2 Hz), 7.60 (1H, t,J=7.2 Hz), 7.73 (1H, d, J=7.2 Hz), 10.4 (1H, brs).

MS: m/z=295 [M+H]⁺.

Third Step

Compound 626C (8.0 g, 27.1 mmol) was suspended in acetonitrile (40 mL),and sodium iodide (12.1 g, 81.0 mmol) was added. Into the reactionsolution was put BF3 etherate (5.16 ml, 40.7 mmol) at once, and themixture was stirred at the same temperature for 30 minutes. To thereaction solution was added ice water and a 10% aqueous sodium sulfitesolution, and the mixture was extracted with ethyl acetate. The extractwas washed with an aqueous saturated sodium chloride solution, anddried. The solvent was distilled off, and the resulting oil wassolidified by adding diisopropyl ether to obtain 5.0 g of compound 626D.

¹H-NMR (CDCl₃) δ: 4.11 (2H, s), 7.22-7.34 (8H, m).

MS: m/z=277 [M−H]⁺.

Fourth Step

Compound 626D (2.5 g, 9.0 mmol) was put into 20 g of polyphosphoric acidheated to 120° C. over 60 minutes. Thereafter, the mixture was stirredat the same temperature for 6 hours. After the reaction solution wascooled to room temperature, and the mixture was put into ice water andextracted with ethyl acetate. The extract was washed with an aqueoussaturated sodium chloride solution, and dried. The solvent was distilledoff, and the resulting oil was purified by silica gel columnchromatography. The materials were eluted firstly with n-hexane and,then, with n-hexane-ethyl acetate (1:1, v/v). An objective fraction wasconcentrated, and solidified by adding hexane to obtain 710 mg ofcompound 626E as a white solid.

¹H-NMR (CDCl₃) δ: 4.05 (2H, s), 7.20-7.25 (2H, m), 7.32-7.37 (2H, m),7.46 (1H, d, J=7.2 Hz), 7.59 (1H, d, J=7.2 Hz), 8.16 (1H, d, J=7.2 Hz).

MS: m/z=261 [M−H]⁺.

Fifth Step

A tetrahydrofuran (10 mL) solution of compound 626E (730 mg, 2.80 mmol)was cooled to 1 to 3° C., and lithium borohydride (61 mg, 2.80 mmol) wasput while the same temperature was retained. The mixture was stirred atthe same temperature for 30 minutes. To the reaction solution was addedice water and a 10% aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The extract was washed with an aqueoussaturated sodium chloride solution, and dried. The solvent was distilledoff, and the resulting oil was solidified by adding diisopropyl ether toobtain 530 mg of compound 626F.

¹H-NMR (CDCl₃) δ: 2.48 (1H, d, J=5.3 Hz), 4.31 (1H, d, J=11.2 Hz), 4.48(1H, d, J=11.2 Hz), 6.14 (1H, d, J=5.3 Hz), 7.03-7.46 (7H, m).

Hereinbelow, according to Reference example 592, compound 626 wassynthesized by the same procedure.

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=6.9 Hz), 3.92 (1H, d, J=7.8 Hz), 4.40(1H, d, J=7.8 Hz), 5.08 (1H, d, J=7.8 Hz), 5.39-5.52 (1H, m), 5.60-5.65(2H, m), 5.76 (1H, d, J=6.9 Hz), 6.96-7.01 (1H, m), 7.17-7.55 (7H, m),8.31 (1H, s).

Reference Example 627

MS: m/z=530 [M+H]⁺. RT=2.08 min.

Reference Example 628

MS: m/z=530 [M+H]⁺. RT=2.21 min.

Reference Example 629

MS: m/z=430 [M+H]⁺. RT=1.64 min.

Reference Example 630

MS: m/z=498 [M+H]⁺. RT=2.43 min.

Reference Example 631

MS: m/z=484 [M+H]⁺. RT=2.24 min.

Reference Example 632

MS: m/z=498 [M+H]⁺. RT=2.35 min.

Reference Example 633

MS: m/z=488 [M+H]⁺. RT=2.12 min.

Reference Example 634

MS: m/z=488 [M+H]⁺. RT=2.17 min.

Reference Example 635

MS: m/z=498 [M+H]⁺. RT=2.40 min.

Reference Example 636

MS: m/z=506 [M+H]⁺. RT=2.17 min.

Reference Example 637

MS: m/z=538 [M+H]⁺ RT=2.46 min.

Reference Example 638

MS: m/z=506 [M+H]⁺ RT=2.21 min.

Reference Example 639

MS: m/z=504 [M+H]⁺ RT=2.36 min.

Reference Example 640

MS: m/z=506 [M+H]⁺ RT=2.17 min.

Reference Example 641

MS: m/z=504 [M+H]⁺ RT=2.36 min.

Reference Example 642

¹H-NMR (CDCl₃) δ: 1.47-1.58 (1H, m), 1.62-1.75 (2H, m), 1.82-1.92 (1H,m), 2.83-2.91 (1H, m), 3.00-3.11 (1H, m), 3.15 (3H, s), 3.18-3.24 (1H,m), 3.47-3.72 (2H, m), 4.08-4.23 (2H, m), 4.36-4.54 (2H, m), 4.92 (1H,s), 5.79 (1H, d, J=7.5 Hz), 6.60-6.68 (2H, m), 6.93 (1H, t, J=7.2 Hz),7.10-7.39 (6H, m).

Reference Example 643

¹H-NMR (CDCl₃) δ: 1.47-1.56 (1H, m), 1.59-1.72 (2H, m), 1.81-1.91 (1H,m), 2.83 (1H, ddd, J=4.2 Hz, 4.2 Hz, 14.7 Hz), 3.00-3.11 (1H, m), 3.16(3H, s), 3.19-3.26 (2H, m), 3.47-3.57 (1H, m), 3.77-3.91 (1H, m),4.16-4.34 (2H, m), 4.40-4.45 (1H, m), 4.96 (1H, s), 5.86 (1H, d, J=7.8Hz), 6.63-6.71 (2H, m), 6.82-6.85 (1H, m), 6.91-6.98 (1H, m), 7.00-7.04(1H, m), 7.11-7.15 (1H, m).

Reference Example 644

MS: m/z=517 [M+H]⁺.

Reference Example 645

MS: m/z=528 [M+H]⁺

Reference Example 646

First Step

Compound 646A (100 mg, 0.33 mmol) was dissolved in acetone (1mL)-toluene (1 mL), acetic acid (0.02 mL, 0.33 mmol) was added, and themixture was heated to reflux for 2 hours. The reaction solution wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography. The materials were eluted firstly withchloroform and, then, with chloroform-methanol (10 1, v/v).Concentration of an objective fraction afforded 117 mg of compound 646Bas an oil.

¹H-NMR (CDCl₃) δ: 1.10 (6H, d, J=6.6 Hz), 1.95 (3H, s), 2.17 (3H, s),4.01 (1H, q, J=14.3 Hz), 5.30 (2H, s), 6.36 (1H, brs), 6.45 (1H, d,J=7.6 Hz), 6.92 (1H, d, J=7.6 Hz), 7.29-7.40 (5H, m).

Second Step

A DMF (170 mL) solution of compound 646B was ice-cooled to 1 to 3° C.,and benzyl bromide (0.11 mL, 0.92 mmol) and cesium carbonate (301 mg,0.92 mmol) were added. After the reaction solution was stirred at roomtemperature for 3 hours, the mixture was distributed between ethylacetate and water. The ethyl acetate layer was separated, and theaqueous layer was extracted with ethyl acetate once. The combinedextracts were sequentially washed with water two times and an aqueoussaturated sodium chloride solution, and dried. The solvent was distilledoff, and the resulting oil was purified by silica gel columnchromatography. The materials were eluted firstly with chloroform and,then, with chloroform-methanol (10:1, v/v). Concentration of anobjective fraction afforded 10 mg of compound 646C as an oil.

MS: m/z=432 [M+H]⁺

Third Step

Compound 646C (10 mg, 0.023 mmol) was dissolved in MeOH (0.5 mL), 10%Pd—C (2.5 mg) was added, and the mixture was subjected to a catalyticreduction reaction under hydrogen stream. The catalyst was removed byfiltration, and the filtrate was concentrated. The resulting residue waspurified by diol silica gel column chromatography. The materials wereeluted firstly with chloroform and, then, with chloroform-methanol(10:1, v/v). Concentration of an objective fraction afforded 3.4 mg ofcompound 646 as an oil.

MS: m/z=342 [M+H]⁺.

Reference Example 647

¹H-NMR (DMSO-d₆) δ: 1.03-1.30 (3H, m), 4.51 (1H, t, J=14.41 Hz),5.12-5.55 (4H, m), 7.18-7.46 (9H, m), 7.58-7.69 (2H, m).

MS: m/z=444.15 [M+H]⁺.

Reference Example 648

¹H-NMR (DMSO-d₆) δ: 1.12-1.35 (2H, m), 4.46-4.55 (1H, m), 5.24-5.61 (3H,m), 6.33-6.42 (1H, m), 7.23-7.67 (8H, m), 8.22-8.29 (1H, m).

MS: m/z=512.15 [M+H]⁺.

Reference Example 649

MS: m/z=480.15 [M+H]⁺.

Reference Example 650

MS: m/z=520 [M+H]⁺. RT=2.21 min.

Reference Example 651

MS: m/z=487 [M+H]⁺. RT=2.04 min.

Reference Example 652

MS: m/z=478 [M+H]⁺. RT=2.04 min.

LCMS Method

Column: ACQUITY UPLC registered trademark BEH C18 (1.7 μm i.d. 2.1×50mm) (Waters)Flow rate: 0.8 mL/min.UV detection wavelength: 254 nmMobile phase: an aqueous solution containing 0.1% formic acid for [A],an acetonitrile solution containing 0.1% formic acid for [B]Gradient: a linear gradient of 10% to 100% solvent [B] over 3.5 minuteswas performed, and 100% solvent [B] was retained for 0.5 minutes.

Reference Example 653

¹H-NMR (CDCl₃) δ: 1.45 (3H, d, J=7.4 Hz), 3.69 (1H, d, J=13.7 Hz), 4.52(1H, d, J=12.6 Hz), 5.14-5.20 (2H, m), 5.32-5.45 (1H, m), 5.64 (1H, d,J=13.5 Hz), 5.74 (1H, d, J=7.7 Hz), 6.56 (1H, d, J=7.7 Hz), 6.81 (1H,ddd, J=7.8, 7.8, 3.9 Hz), 6.87-6.96 (2H, m), 7.11 (1H, ddd, J=8.2, 8.2,2.6 Hz), 7.17 (1H, d, J=7.7 Hz), 7.32 (1H, dd, J=8.4, 5.4 Hz).

MS: m/z=524 [M+H]⁺.

Reference Example 654

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=7.4 Hz), 3.62 (1H, d, J=13.5 Hz), 4.44(1H, d, J=12.9 Hz), 4.86 (1H, d, J=13.2 Hz), 5.43-5.56 (1H, m), 5.68(1H, d, J=13.5 Hz), 5.83 (1H, d, J=7.7 Hz), 5.94 (1H, s), 6.81-6.91 (2H,m), 7.07-7.18 (3H, m), 7.26 (1H, t, J=7.7 Hz), 7.34 (1H, d, J=7.4 Hz),7.55 (1H, d, J=8.0 Hz).

MS: m/z=566, 568 [M+H]⁺.

Reference Example 655

¹H-NMR (CDCl₃) δ: 1.44 (3H, d, J=7.4 Hz), 4.07 (1H, d, J=14.6 Hz), 4.52(1H, d, J=12.6 Hz), 5.13 (1H, d, J=12.6 Hz), 5.34-5.47 (2H, m), 5.79(1H, d, J=7.7 Hz), 5.93 (1H, d, J=14.6 Hz), 6.58 (1H, d, J=7.7 Hz), 6.82(1H, ddd, J=7.9, 7.9, 5.6 Hz), 6.89-6.97 (1H, m), 7.14 (1H, d, J=7.7Hz), 7.40 (2H, d, J=5.2 Hz), 7.76-7.83 (1H, m).

MS: m/z=573 [M+H]⁺.

Reference Example 656

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=7.4 Hz), 3.72 (1H, d, J=13.7 Hz), 4.48(1H, d, J=13.2 Hz), 4.90 (1H, d, J=13.2 Hz), 5.13 (1H, s), 5.50-5.58(1H, m), 5.61 (1H, d, J=14.0 Hz), 5.86 (1H, d, J=7.7 Hz), 6.56 (1H, d,J=7.7 Hz), 6.84 (1H, ddd, J=7.9, 7.9, 5.6 Hz), 6.91-7.00 (2H, m),7.11-7.19 (2H, m), 7.40 (1H, dd, J=8.4, 5.4 Hz).

MS: m/z=524 [M+H]⁺.

Reference Example 657

¹H-NMR (CDCl₃) δ: 1.45 (3H, d, J=7.3 Hz), 3.97 (1H, d, J=14.5 Hz), 4.53(1H, d, J=12.7 Hz), 5.12 (1H, d, J=12.7 Hz), 5.32 (1H, s), 5.35-5.49(1H, m), 5.76 (1H, d, J=7.6 Hz), 5.90 (1H, d, J=14.5 Hz), 6.73 (1H, d,J=7.6 Hz), 6.78-6.86 (1H, m), 7.03-7.14 (2H, m), 7.19 (1H, dd, J=7.7,0.8 Hz), 7.36-7.43 (2H, m), 7.77 (1H, dd, J=6.3, 2.9 Hz).

MS: m/z=556 [M+H]⁺.

Reference Example 658

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.1 Hz), 3.74 (1H, d, J=13.7 Hz), 4.47(1H, d, J=12.9 Hz), 4.90 (1H, d, J=13.2 Hz), 5.13 (1H, s), 5.47-5.60(1H, m), 5.65 (1H, d, J=13.7 Hz), 5.86 (1H, d, J=7.7 Hz), 6.68 (1H, d,J=7.7 Hz), 6.81 (1H, dd, J=7.8, 7.8 Hz), 6.94 (1H, dd, J=8.5, 2.5 Hz),7.10-7.20 (2H, m), 7.27-7.31 (1H, m), 7.39 (1H, dd, J=8.4, 5.4 Hz).

MS: m/z=540 [M+H]⁺.

Reference Example 659

¹H-NMR (CDCl₃) δ: 1.45 (3H, d, J=7.1 Hz), 4.31 (1H, d, J=14.0 Hz), 4.53(1H, d, J=12.6 Hz), 5.15 (1H, d, J=12.6 Hz), 5.21 (1H, s), 5.31-5.45(1H, m), 5.64 (1H, d, J=14.0 Hz), 5.80 (1H, d, J=7.7 Hz), 6.51 (1H, ddd,J=8.0, 8.0, 2.6 Hz), 6.70 (1H, dd, J=8.4, 5.6 Hz), 6.80 (1H, dd, J=9.3,2.5 Hz), 7.10 (1H, d, J=7.7 Hz), 7.15-7.25 (2H, m), 7.51 (1H, d, J=8.0Hz).

MS: m/z=540 [M+H]⁺.

Reference Example 660

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=7.4 Hz), 4.09 (1H, d, J=14.6 Hz), 4.44(1H, d, J=13.2 Hz), 4.92 (1H, d, J=13.5 Hz), 5.32 (1H, s), 5.48-5.60(1H, m), 5.85-5.95 (2H, m), 6.56 (1H, d, J=7.7 Hz), 6.85 (1H, ddd,J=8.0, 8.0, 5.6 Hz), 6.92-7.00 (1H, m), 7.11 (1H, d, J=7.7 Hz),7.39-7.44 (2H, m), 7.80-7.87 (1H, m).

MS: m/z=574 [M+H]⁺.

Reference Example 661

MS: m/z=566, 568 [M+H]⁺.

Reference Example 662

MS: m/z=502 [M+H]⁺.

Reference Example 663

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.1 Hz), 4.33 (1H, d, J=14.0 Hz), 4.48(1H, d, J=13.2 Hz), 4.90 (1H, d, J=12.6 Hz), 5.16 (1H, s), 5.46-5.59(1H, m), 5.62 (1H, d, J=13.7 Hz), 5.90 (1H, d, J=7.7 Hz), 6.54 (1H, ddd,J=7.7, 7.7, 2.5 Hz), 6.69 (1H, dd, J=8.7, 5.6 Hz), 6.84 (1H, dd, J=9.3,2.5 Hz), 7.11 (1H, d, J=7.7 Hz), 7.15 (1H, d, J=7.7 Hz), 7.23 (1H, dd,J=7.8, 7.8 Hz), 7.55 (1H, d, J=8.0 Hz).

MS: m/z=540 [M+H]⁺.

Reference Example 664

¹H-NMR (CDCl₃) δ: 1.45 (3H, d, J=7.1 Hz), 3.71 (1H, d, J=13.7 Hz), 4.52(1H, d, J=12.6 Hz), 5.13-5.19 (2H, m), 5.32-5.45 (1H, m), 5.68 (1H, d,J=13.7 Hz), 5.74 (1H, d, J=7.7 Hz), 6.68 (1H, dd, J=7.7, 1.4 Hz), 6.78(1H, dd, J=7.8, 7.8 Hz), 6.92 (1H, d, J=9.1 Hz), 7.07-7.18 (2H, m), 7.24(1H, dd, J=8.0, 1.4 Hz), 7.32 (1H, dd, J=8.2, 5.5 Hz).

MS: m/z=540 [M+H]⁺.

Reference Example 665

¹H-NMR (CDCl₃) δ: 0.92 (3H, d, J=7.1 Hz), 2.35 (3H, s), 3.60 (1H, d,J=13.5 Hz), 4.49 (1H, d, J=12.9 Hz), 4.82 (1H, d, J=12.4 Hz), 5.39-5.51(2H, m), 5.60 (1H, d, J=13.5 Hz), 5.85 (1H, d, J=7.7 Hz), 6.69 (1H, d,J=7.4 Hz), 6.79-6.87 (1H, m), 7.05 (1H, d, J=7.7 Hz), 7.10-7.15 (3H, m),7.22 (1H, d, J=7.1 Hz), 7.27-7.33 (1H, m).

MS: m/z=502 [M+H]⁺.

Methods for synthesizing intermediate compounds i-1 to i-72 forsynthesizing parent compounds are shown below.

Synthesis of Intermediate Compound i-3

Step 1

Compound i-1 (50.0 g, 136 mmol) was dissolved in dichloromethane (500mL), Boc₂O (34.8 mL, 150 mmol) and DMAP (831 mg, 6.81 mmol) were added,and the mixture was stirred at room temperature for 2 hours. Thereafter,NBS (29.1 g, 163 mmol) was added, and the mixture was further stirred atroom temperature overnight.

The organic layer was washed with water and aqueous saturated sodiumchloride solution, and then dried with anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (hexane-ethylacetate) to obtain compound i-2 (64.0 g, yield 86%).

¹H-NMR (DMSO-d₆) δ: 8.62 (s, 1H), 7.58 (t, J=8.6 Hz, 2H), 7.38 (brs,3H), 5.44 (brs, 1H), 5.23 (d, J=10.6 Hz, 2H), 5.14 (d, J=11.9 Hz, 1H),3.40 (s, 1H), 1.47-1.43 (m, 12H).

Step 2

A methanol (600 mL) solution of compound i-2 (64.0 g, 117 mmol) wascooled to 0° C. with ice water. A 2 mol/L aqueous sodium hydroxidesolution (76 mL, 152 mmol) was added thereto, and the mixture wasstirred at 0° C. for 1 hour. Under an ice bath, the mixture wasneutralized with 2 mol/L hydrochloric acid, and the precipitated solidwas separated by filtration. The solid was washed with water, and driedto obtain compound i-3 (40.5 g, yield 78%).

¹H-NMR (DMSO-d₆) δ: 8.38 (s, 1H), 7.62 (t, J=6.6 Hz, 1H), 7.53 (d, J=7.1Hz, 2H), 7.35-7.33 (m, 3H), 5.29 (brs, 1H), 5.11 (q, J=12.5 Hz, 2H),4.75 (t, J=6.9 Hz, 1H), 4.65 (t, J=11.1 Hz, 1H), 1.45 (d, J=7.1 Hz, 3H).

Synthesis of Intermediate Compound i-5

Step 1

To compound i-4 (6.60 g, 9.55 mmol), dioxane (66 mL), Pd₂(PPh₃)₂ (670mg, 0.955 mmol), and tributyl(1-ethoxy-vinyl)tin (4.84 mL, 14.3 mmol)were added under nitrogen atmosphere, and the mixture was heated toreflux for 2 hours and 30 minutes. After cooling the mixture to roomtemperature, 1 mol/L hydrochloric acid (20 mL) was added, and themixture was stirred at room temperature for 20 minutes. Water was added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and aqueous saturated sodium chloride solution, andthen dried with anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and the resulting residue was purified bysilica gel column chromatography (hexane-ethyl acetate) to obtaincompound i-5 (5.50 g, yield 88%).

¹H-NMR (DMSO-d₆) δ: 7.75 (s, 1H), 7.59 (d, J=6.6 Hz, 2H), 7.50 (s, 1H),7.42-7.39 (m, 5H), 7.11 (s, 2H), 6.80 (s, 1H), 6.54 (d, J=7.1 Hz, 1H),5.74 (s, 1H), 5.64 (d, J=13.4 Hz, 1H), 5.57 (brs, 1H), 5.45 (d, J=10.6Hz, 1H), 5.25 (d, J=10.6 Hz, 1H), 5.12 (d, J=13.6 Hz, 1H), 4.52 (d,J=13.6 Hz, 1H), 3.96 (d, J=13.6 Hz, 1H), 2.37 (s, 3H), 1.02 (d, J=6.3Hz, 3H).

Synthesis of Intermediate Compound i-7

Step 1

To compound i-6 (40 mg, 0.058 mmol) were added dimethylacetamide (0.5mL) and copper(I) cyanide (52 mg, 0.579 mmol), and the mixture washeated to stir in a sealed tube at 140° C. for 26 hours. 1 mol/Lhydrochloric acid (20 mL) was added, and the mixture was extracted withethyl acetate. The organic layer was washed with aqueous saturatedsodium chloride solution, and then dried with anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the resultingresidue was purified by preparative LCMS (method 14) to obtain compoundi-7 (8.0 mg, yield 25%).

¹H-NMR (DMSO-d₆) δ: 7.58 (s, 1H), 7.51 (s, 1H), 7.46 (s, 2H), 7.21 (brs,2H), 6.92-6.88 (m, 2H), 5.86 (s, 1H), 5.65 (d, J=12.6 Hz, 1H), 5.48(brs, 1H), 4.95 (brs, 1H), 4.49 (brs, 1H), 3.97 (d, J=13.4 Hz, 2H), 1.02(s, 3H).

Synthesis of Intermediate Compound i-10

Step 1

To compound i-8 (110 mg, 0.164 mmol) were added methanol (1 mL),tetrahydrofuran (1 mL), and 2 mol/L aqueous sodium hydroxide solution(0.246 mL, 0.492 mmol), and the mixture was stirred at 60° C. for 3hours, then 2 mol/L aqueous sodium hydroxide solution (0.164 mL, 0.328mmol) was further stirred at 60° C. for 4 hours. The mixture wasneutralized with 2 mol/L hydrochloric acid, and then extracted withchloroform. The organic layer was washed with aqueous saturated sodiumchloride solution, and then dried with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain compound i-9(91 mg, 98%).

MS: m/z=566 [M+H]⁺. RT=2.30 min.

Step 2

To compound i-9 (20 mg, 0.035 mmol) were added dimethylformamide (0.5mL), 2 mol/L ammonia-methanol solution (0.053 mL, 0.106 mmol),[4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride](29.3 mg, 0.106 mmol), and the mixture was stirred at room temperatureovernight. Thereafter, a 28% sodium methoxide-methanol solution (34.1mg, 0.177 mmol) was added, and the mixture was further stirred at roomtemperature for 1 hour. After adding 0.5 mol/L hydrochloric acid, themixture was extracted with ethyl acetate. The organic layer was washedwith aqueous saturated sodium chloride solution, and then dried withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was purified by preparative LCMS(method 14) to obtain compound i-10 (4.0 mg, yield 20%).

MS: m/z=565 [M+H]⁺. RT=2.03 min.

Synthesis of Intermediate Compound i-12

Step 1

To compound i-11 (1.00 g, 3.28 mmol) were added tetrahydrofuran (25 mL),[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (214mg, 4.91 mmol), potassium cyclopropyltrifluoroborate (727 mg, 4.91mmol), and a 2 mol/L aqueous sodium carbonate solution (4.91 mL, 9.83mmol) under nitrogen atmosphere, and the mixture was heated to refluxfor 20 hours. After adding water, the mixture was extracted with ethylacetate. The organic layer was washed with water and aqueous saturatedsodium chloride solution, and then dried with anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel column chromatography(hexane-chloroform) to obtain compound i-12 (350 mg, yield 24%).

MS: m/z=267 [M+H]⁺. RT=2.46 min.

Synthesis of Intermediate Compound i-14

Step 1

To compound i-13 (200 mg, 0.305 mmol) were added tetrahydrofuran (3 mL),bis(pinacolato)diboron (232 mg, 0.914 mmol), PdC₂(dppf).CH₂Cl₂ (24.9 mg,0.030 mmol), and potassium acetate (90 mg, 0.914 mmol), and the mixturewas stirred at 80° C. for 3 hours and 30 minutes. After cooled to roomtemperature, the mixture was filtered with celite, and the solvent wasdistilled off under reduced pressure. After adding 1 mol/L hydrochloricacid, the mixture was extracted with ethyl acetate. The organic layerwas washed with aqueous saturated sodium chloride solution, and thendried with anhydrous sodium sulfate. To the obtained brown substancewere added dimethylacetamide (2 mL) and lithium chloride (64.5 mg, 1.53mmol), and the mixture was stirred at 100° C. for 4 hours. After cooledto room temperature, 1 mol/L hydrochloric acid was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith aqueous saturated sodium chloride solution, and then dried withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was purified by preparative LCMS(method 14) to obtain compound i-14 (59 mg, yield 37%).

MS: m/z=532 [M+H]⁺. RT=2.02 min.

Synthesis of Intermediate Compound i-16

Step 1

To compound i-15 (20 mg, 0.030 mmol) were added tetrahydrofuran (0.5mL), PEPPSI-IPr (2.07 mg, 3.05 μmol), and 2 mol/L methyl zincchloride-tetrahydrofuran solution (0.076 mL, 0.152 mmol), and themixture was heated to stir in a sealed tube at 100° C. for 3 hours undernitrogen stream. After cooled to room temperature, 2 mol/L hydrochloricacid was added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with aqueous saturated sodium chloridesolution, and then dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (DIOL, hexane-ethylacetate) to obtain compound i-16 (4.0 mg, yield 26%).

¹H-NMR (DMSO-d₆) δ: 7.54 (s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.25 (s,2H), 7.08 (s, 2H), 6.91 (s, 1H), 6.81 (s, 1H), 5.68 (d, J=13.1 Hz, 1H),5.56 (s, 1H), 5.48 (s, 1H), 5.05 (d, J=13.6 Hz, 1H), 4.41 (d, J=12.6 Hz,1H), 3.87 (d, J=12.9 Hz, 1H), 1.52 (s, 3H), 1.18 (d, J=6.3 Hz, 3H).

Synthesis of Intermediate Compound i-18

Step 1

Compound i-17 (50 mg, 0.076 mmol) was dissolved in tetrahydrofuran (1mL), and the mixture was cooled to −78° C. with dry ice-acetone. A 1.06mol/L diisobutylaluminum hydride-hexane solution (0.108 mL, 0.115 mmol)was added thereto, and the mixture was stirred at −78° C. for 1 hour. Asaturated Rochelle salt solution was added, and the mixture was stirredat room temperature for 20 minutes and then extracted with ethylacetate. The organic layer was washed with aqueous saturated sodiumchloride solution, and then dried with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (hexane-ethylacetate) to obtain compound i-18 (35 mg, yield 70%).

¹H-NMR (DMSO-d₆) δ: 7.53 (s, 3H), 7.46 (s, 2H), 7.36 (d, J=7.3 Hz, 3H),7.29 (s, 1H), 7.15 (s, 2H), 6.80 (brs, 1H), 6.47 (d, J=7.1 Hz, 1H), 5.70(s, 1H), 5.61 (d, J=14.4 Hz, 1H), 5.53 (brs, 1H), 5.33 (d, J=11.1 Hz,1H), 5.13 (d, J=11.4 Hz, 1H), 5.01 (d, J=12.9 Hz, 1H), 4.92 (s, 1H),4.57 (s, 1H), 4.47 (d, J=13.9 Hz, 1H), 3.98 (d, J=13.9 Hz, 1H), 0.98 (d,J=6.8 Hz, 3H), 0.71 (d, J=5.3 Hz, 3H).

Synthesis of Intermediate Compound i-20

Step 1

To compound i-19 (560 mg, 1.43 mmol) were added toluene (250 mL), aceticacid (25 mL), and tosyl acid monohydrate (54.4 mg, 0.286 mmol), and themixture was heated to reflux for 16 hours. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (hexane-ethyl acetate) to obtain compound i-20(210 mg, yield 45%).

¹H-NMR (DMSO-d₆) δ: 7.56 (d, J=6.8 Hz, 2H), 7.36-7.27 (m, 5H), 6.23 (d,J=7.3 Hz, 1H), 5.06 (s, 2H), 4.79 (t, J=11.7 Hz, 1H), 4.14 (d, J=13.4Hz, 1H), 4.02 (brs, 2H), 3.43 (t, J=13.0 Hz, 1H), 3.13 (t, J=10.5 Hz,1H), 2.95 (t, J=11.1 Hz, 1H).

Synthesis of Intermediate Compound i-25

Step 1

Compound i-21 (30.0 g, 104 mmol) was suspended in methanol (450 mL), anddissolved by heating to 65° C. Manganese dioxide (75 g, 863 mmol) wasadded, and the mixture was stirred at 65° C. for 2 hours. The solid wasremoved by filtration, and the filtrate was distilled off under reducedpressure. To the resulting residue were addedtetrahydrofuran-diisopropyl ether to precipitate a solid, then the solidwas filtered to obtain compound i-22 (27.55 g, yield 93%).

¹H-NMR (CDCl₃) δ: 3.99 (s, 3H), 5.43 (s, 2H), 7.27-7.45 (m, 6H), 8.62(s, 1H), 10.05 (s, 1H).

Step 2

Sodium chlorite (34.6 g, 383 mmol) was dissolved in water (150 mL), andthe mixture was cooled to 0° C. with ice water. Amidosulfuric acid (37.2mg, 383 mmol) was added thereto, and the mixture was stirred for 40minutes. Compound i-22 (27.5 g, 96 mmol) was dissolved intetrahydrofuran (450 mL) and DMF (45 mL) in another flask, and themixture was cooled to 0° C. with ice water. The aqueous solutionprepared as above was added dropwise thereto, and the mixture wasstirred at 0° C. for 1 hour. The solvent was concentrated under reducedpressure, water and diisopropyl ether were added, and the solid wasfiltered to obtain compound i-23 (19.49 g, yield 67%).

¹H-NMR (DMSO-d₆) δ: 3.74 (s, 3H), 5.11 (s, 2H), 7.27-7.40 (m, 4H),7.44-7.50 (m, 2H), 8.11 (s, 1H).

Step 3

Compound i-23 (14.0 g, 46.2 mmol) was dissolved in DMF (140 mL), and thesolution was ice-cooled. (R)-1,1,1-trifluoroisopropylamine hydrochloride(10.36 g, 69.2 mmol), EDC (11.50 g, 60.0 mmol), HOBt (8.11 g, 60.0mmol), and triethylamine (19.2 mL, 138 mmol) were added, and the mixturewas stirred at room temperature for 4 hours. Water was added to thereaction solution to stop the reaction. The solution was extracted withethyl acetate, and the organic layer was washed with water and aqueoussaturated sodium chloride solution, and then dried with anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the resulting residue was purified by silica gel chromatography(chloroform-methanol) to obtain compound i-24 (12.87 g, yield 70%).

MS: m/z=399.1 [M+H]⁺.

Step 4

Compound i-24 (12.55 g, 31.5 mmol) was dissolved in DMF (130 mL).Potassium carbonate (21.77 g, 158 mmol) was added, and the mixture wasstirred for 15 minutes. 2,4-dinitrophenylhydroxylamine (9.41 g, 47.3mmol) was added, and the mixture was stirred for 3 hours. To thereaction solution was added chloroform, the precipitated solid wasremoved by filtration, and the filtrate was distilled off under reducedpressure. To the resulting DMF solution were added paraformaldehyde (851mg, 28.3 mmol) and acetic acid (0.09 mL, 1.58 mmol), and the mixture wasstirred at 110° C. for 3 hours and 30 minutes. The reaction solution wasallowed to cool, the solvent was distilled off under reduced pressure,and the resulting residue was purified by silica gel chromatography(chloroform-methanol) to obtain compound i-25 (8.15 g, yield 61%).

¹H-NMR (CDCl₃) δ: 1.32 (d, J=7.2 Hz, 3H), 3.79 (s, 3H), 4.39-4.54 (m,2H), 5.14 (d, J=10.2 Hz, 1H), 5.24 (m, 1H), 5.28 (d, J=10.2 Hz, 1H),6.54 (m, 1H), 7.25-7.33 (m, 3H), 7.45-7.52 (m, 2H), 8.18 (s, 1H).

Synthesis of Intermediate Compound i-29

Step 1

Compound i-25 (1.5 g, 3.5 mmol) was suspended in dichloromethane. Boc₂O(0.86 mL, 3.7 mmol) and DMAP (43 mg, 0.35 mmol) were added, and themixture was stirred at room temperature for 1 hour. Water was added, andthe mixture was extracted with chloroform. The organic layer was washedwith water and aqueous saturated sodium chloride solution, and thendried with anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel chromatography (hexane-ethyl acetate) to obtain compound i-26 (1.59g, yield 86%).

¹H-NMR (CDCl₃) δ: 1.33-1.50 (m, 12H), 3.91 (s, 3H), 4.71 (m, 0.6H), 4.88(m, 0.4H), 5.13-5.60 (m, 4H), 7.27-7.37 (m, 3H), 7.49-7.66 (m, 2H), 8.16(s, 1H).

Step 2

Compound i-26 (1.5 g, 2.9 mmol) was suspended in toluene (30 mL) undernitrogen atmosphere, and the mixture was cooled to −78° C. with dryice-acetone. A DIBAL-hexane solution (3.0 mL, 3.1 mmol) was addeddropwise thereto, and the mixture was stirred at −78° C. for 1 hour. Tothe reaction solution was added ethyl acetate to stop the reaction, andthe mixture was heated to room temperature. An aqueous potassium sodiumtartrate solution was added, and the mixture was stirred vigorously atroom temperature for 1 hour. Two layers were separated, and the organiclayer was washed with water and aqueous saturated sodium chloridesolution, and then dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting residue waspurified by silica gel chromatography (hexane-ethyl acetate) to obtaincompound i-27 (568 mg, yield 40%).

¹H-NMR (CDCl₃) δ: 1.38-1.49 (m, 12H), 4.58-4.81 (m, 1H), 5.23-5.70 (m,4H), 7.27-7.40 (m, 3H), 7.47-7.65 (m, 2H), 7.95 (s, 1H), 10.32 (s, 1H).

Step 3

Compound i-27 (550 mg, 1.1 mmol) was dissolved in dichloromethane (11mL). The solution was ice-cooled, bis(2-methoxyethyl)aminosulfurtrifluoride (0.72 mL, 3.9 mmol) was added, and the mixture was heated toroom temperature and stirred for 2 hours. Water was added to thereaction solution to stop the reaction, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated sodiumbicarbonate water, water, and aqueous saturated sodium chloridesolution, and then dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting residue waspurified by silica gel chromatography (hexane-ethyl acetate) to obtaincompound i-28 (408 mg, yield 71%).

¹H-NMR (CDCl₃) δ: 1.36-1.52 (m, 12H), 4.68 (m, 0.7H), 4.78 (m, 0.3H),5.18-5.59 (m, 4H), 6.89 (t, J=54.9 Hz, 1H), 7.27-7.38 (m, 3H), 7.47-7.63(m, 2H), 7.64 (s, 1H).

Step 4

Compound i-28 (400 mg, 0.77 mmol) was dissolved in methanol (6 mL). Thesolution was ice-cooled, a 2 mol/L aqueous sodium hydroxide solution(0.5 mL, 1.0 mmol) was added, and the mixture was stirred at 0° C. for 1hour. The reaction solution was diluted by adding water, and the mixturewas extracted with chloroform. The organic layer was washed with waterand aqueous saturated sodium chloride solution, and then dried withanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain compound i-29 (286 mg, yield 89%).

¹H-NMR (CDCl₃) δ: 1.38 (d, J=7.2 Hz, 3H), 4.47 (d, J=7.8 Hz, 2H), 5.22(d, J=10.2 Hz, 1H), 5.29 (m, 1H), 5.34 (d, J=10.2 Hz, 1H), 5.82 (m, 1H),6.80 (t, J=55.2 Hz, 1H), 7.28-7.37 (m, 3H), 7.48-7.55 (m, 2H), 7.71 (s,1H).

Synthesis of Intermediate Compound i-32

Step 1

Compound i-30 (13.3 g, 69.9 mmol) was dissolved in DMF (60 mL). Thesolution was ice-cooled, sodium hydride (3.3 g, 83 mmol) was added, andthe mixture was stirred at 0° C. for 15 minutes. Bromoacetaldehydedimethyl acetal (12.3 mL, 104 mmol) and potassium iodide (1.16 g, 7.0mmol) were added thereto, and the mixture was stirred at roomtemperature for 3 hours. Water was added to the reaction solution tostop the reaction, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and aqueous saturated sodiumchloride solution, and then dried with anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel chromatography (hexane-ethyl acetate)to obtain compound i-31 (8.8 g, yield 45%).

¹H-NMR (CDCl₃) δ: 3.34 (s, 6H), 3.53 (d, J=5.1 Hz, 2H), 3.76 (t, J=5.7Hz, 2H), 3.91 (t, J=5.7 Hz, 2H), 4.44 (t, J=5.1 Hz, 1H), 7.72 (m, 2H),7.85 (m, 2H).

Step 2

Compound i-31 (8.79 g, 31.5 mmol) was dissolved in ethanol (100 mL).Hydrazine monohydrate (3.0 mL, 62.9 mmol) was added, and the mixture wasstirred at 60° C. for 2 hours. After cooling, the precipitated solid wasremoved by filtration, and the filtrate was distilled off under reducedpressure. The reprecipitated solid was removed by filtration, and thefiltrate was distilled off under reduced pressure to obtain compoundi-32 (4.37 g, yield 93%).

¹H-NMR (CDCl₃) δ: 2.87 (m, 2H), 3.40 (s, 6H), 3.49-3.57 (m, 4H), 4.53(m, 1H).

Synthesis of Intermediate Compounds i-36 and i-37

Step 1

Compound i-33 (1.00 g, 4.09 mmol) was dissolved in DMF (5 mL),dimethylamine hydrochloride (384 mg, 4.71 mmol), potassium carbonate(651 mg, 4.71 mmol), and triethylamine (0.653 mL, 4.71 mmol) were added,and the mixture was stirred in a sealed tube at 160° C. for 17.5 hours.Water was added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and aqueous saturated sodiumchloride solution, and then dried with anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel chromatography (hexane-ethyl acetate)to obtain compound i-34 (587 mg, yield 53%).

¹H-NMR (CDCl₃) δ: 2.71 (s, 6H), 3.96 (s, 2H), 6.68 (d, J=7.3 Hz, 1H),6.84 (d, J=8.5 Hz, 1H), 7.18-7.36 (m, 4H), 7.99 (dd, J=7.9, 1.5 Hz, 1H).

Step 2

Compound i-34 (587 mg, 2.18 mmol) was dissolved in tetrahydrofuran (20mL), sodium bis(2-methoxyethoxy)aluminiumhydride-toluene solution (3.39mL, 10.9 mmol) was added dropwise under ice-cooling, and the mixture wasstirred at room temperature for 3.5 hours. Under ice-cooling, an aqueousRochelle salt (7.06 g, 25.0 mmol) solution (50 mL) was added, and themixture was heated to room temperature. The solution was extracted withethyl acetate, and the organic layer was washed with aqueous saturatedsodium chloride solution, and then dried with anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel chromatography(hexane-ethyl acetate) to obtain compound i-35 (460 mg, yield 78%).

¹H-NMR (CDCl₃) δ: 2.61 (s, 6H), 3.67 (d, J=13.7 Hz, 1H), 4.95 (d, J=13.7Hz, 1H), 6.61 (d, J=7.1 Hz, 1H), 6.96-7.18 (m, 4H), 7.24-7.28 (m, 2H),7.79 (d, J=7.7 Hz, 1H), 9.88 (d, J=6.6 Hz, 1H).

Step 3

Compound i-35 (100 mg, 0.368 mmol) was dissolved in ethyl acetate (3mL), compound i-A (222 mg, 0.553 mmol) and chloroacetic acid (104 mg,1.11 mmol) were added, and the mixture was stirred in a sealed tube at120° C. for 4 hours. The mixture was diluted with ethyl acetate, washedwith an aqueous saturated sodium bicarbonate solution and water, andthen dried with anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel chromatography (hexane-ethyl acetate) to obtain compound i-36 (107mg, yield 44%) and compound i-37 (42.7 mg, yield 18%).

4: ¹H-NMR (CDCl₃) δ: 0.96 (d, J=7.1 Hz, 3H), 2.48 (s, 6H), 3.49 (d,J=14.0 Hz, 1H), 4.18 (d, J=13.2 Hz, 1H), 4.66 (d, J=13.2 Hz, 1H),5.35-5.52 (m, 2H), 5.59 (d, J=10.4 Hz, 1H), 5.79 (d, J=14.0 Hz, 1H),5.99 (s, 1H), 6.57 (d, J=7.7 Hz, 1H), 6.72 (t, J=7.1 Hz, 1H), 7.03-7.15(m, 4H), 7.26-7.38 (m, 5H), 7.58-7.64 (m, 2H).

5: MS: m/z=655.15 [M+H]⁺.

Synthesis of Intermediate Compound i-42

Step 1

Compound i-38 (12.0 g, 49.1 mmol) was dissolved in tetrahydrofuran (20mL), a sodium methoxide-methanol solution (60.0 mL, 311 mmol) was added,and the mixture was refluxed for 4 hours. An aqueous hydrochloric acidsolution was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and aqueous saturated sodiumchloride solution, and then dried with anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and to the resultingresidue were added dichloromethane-hexane to precipitate a solid, thenthe solid was filtered to obtain compound i-39 (10.5 g, yield 84%).

¹H-NMR (CDCl₃) δ: 3.79 (s, 3H), 3.99 (s, 2H), 6.85 (dd, J=7.8, 6.2 Hz,2H), 7.19-7.26 (m, 2H), 7.30-7.39 (m, 2H), 7.95 (dd, J=8.2, 1.4 Hz, 1H).

Step 2

Compound i-39 was suspended in dichloromethane (100 mL) under nitrogenatmosphere, and a 1 mol/L tribromoborane-dichloromethane solution (82.0mL, 82.0 mmol) was added dropwise under ice-cooling, then the mixturewas stirred at room temperature for 2 hours. An aqueous sodiumbicarbonate solution was added under ice-cooling, and then the mixturewas heated to room temperature. An aqueous saturated sodium chloridesolution was added, and the mixture was extracted with dichloromethane.The organic layer was washed with aqueous saturated sodium chloridesolution, and then dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and to the resulting residue wereadded dichloromethane-hexane to precipitate a solid, then the solid wasfiltered to obtain compound i-40 (8.42 g, yield 85%).

¹H-NMR (CDCl₃) δ: 4.05 (s, 2H), 6.72 (d, J=6.9 Hz, 1H), 6.98 (dd, J=8.2,1.1 Hz, 1H), 7.32-7.48 (m, 4H), 8.29 (dd, J=7.6, 2.1 Hz, 1H), 12.35 (s,1H).

Step 3

Compound i-40 (500 mg, 2.06 mmol) was dissolved in tetrahydrofuran (10mL), sodium bis(2-methoxyethoxy)aluminiumhydride-toluene solution (3.21mL, 10.3 mmol) was added dropwise under ice-cooling, and the mixture wasstirred for 1 hour under ice-cooling. Under ice-cooling, an aqueousRochelle salt (2.82 g, 10.0 mmol) solution (20 mL) was added, and themixture was heated to room temperature. The solution was extracted withethyl acetate, and the organic layer was washed with water and aqueoussaturated sodium chloride solution, and then dried with anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and to the resulting residue were added dichloromethane-hexane toprecipitate a solid, then the solid was filtered to obtain compound i-41(389 mg, yield 77%).

¹H-NMR (CDCl₃) δ: 3.28 (s, 1H), 3.77 (d, J=13.2 Hz, 1H), 4.73 (d, J=13.2Hz, 1H), 6.69 (s, 1H), 6.73-6.78 (m, 2H), 7.06-7.17 (m, 4H), 7.60-7.65(m, 1H), 8.45 (s, 1H).

Step 4

Compound i-41 (150 mg, 0.614 mmol) was suspended in acetonitrile (1.5mL), triethylamine (0.426 mL, 3.07 mmol), acetic acid anhydride (0.290mL, 3.07 mmol) and DMAP (37.5 mg, 0.307 mmol) were added, and themixture was stirred at room temperature for 1.5 hours. Water was added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with an aqueous hydrochloric acid solution and aqueous saturatedsodium chloride solution, and then dried with anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel chromatography (hexane-ethyl acetate)to obtain compound i-42 (171 mg, yield 85%).

¹H-NMR (CDCl₃) δ: 2.03 (s, 3H), 2.41 (s, 3H), 3.55 (d, J=14.0 Hz, 1H),5.38 (d, J=13.9 Hz, 1H), 6.97-7.16 (m, 5H), 7.24 (s, 1H), 7.29 (t, J=7.9Hz, 1H), 7.40 (d, J=7.8 Hz, 1H).

Synthesis of Intermediate Compound i-49

Step 1

Compound i-43 (4.06 g, 16.7 mmol) was dissolved in DMSO (40 mL),potassium phosphate (7.11 g, 33.5 mmol) and allyl bromide (2.18 mL, 25.1mmol) were added, and the mixture was stirred at room temperature for 6hours. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with water and aqueous saturatedsodium chloride solution, and then dried with anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and tothe resulting residue was added hexane to precipitate a solid, then thesolid was filtered to obtain compound i-44 (4.28 g, yield 91%).

¹H-NMR (CDCl₃) δ: 4.00 (s, 2H), 4.50-4.55 (m, 2H), 5.20-5.26 (m, 1H),5.32-5.41 (m, 1H), 5.89-6.03 (m, 1H), 6.84 (d, J=8.0 Hz, 2H), 7.19-7.26(m, 2H), 7.29-7.37 (m, 2H), 7.92 (dd, J=8.2, 1.4 Hz, 1H).

Step 2

Compound i-44 (50.0 mg, 0.177 mmol) was dissolved in DMA (1 mL), and thesolution was stirred in a sealed tube at 230° C. for 6 hours. An aqueoushydrochloric acid solution was added, and the mixture was extracted withethyl acetate. The organic layer was washed with an aqueous hydrochloricacid solution and aqueous saturated sodium chloride solution, and thendried with anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel chromatography (hexane-ethyl acetate) to obtain compound i-45 (37.1mg, yield 74%).

¹H-NMR (CDCl₃) δ: 3.43 (d, J=6.6 Hz, 2H), 4.01 (s, 2H), 5.05-5.15 (m,2H), 6.01 (ddt, J=17.3, 10.1, 6.8 Hz, 1H), 6.65 (d, J=7.4 Hz, 1H), 7.24(d, J=7.7 Hz, 1H), 7.29-7.46 (m, 3H), 8.27 (dd, J=8.0, 1.6 Hz, 1H),12.69 (s, 1H).

Step 3

Compound i-45 (600 mg, 2.13 mmol) was dissolved in DMSO (6 mL),potassium phosphate (902 mg, 4.25 mmol) and allyl bromide (0.276 mL,3.19 mmol) were added, and the mixture was stirred at room temperaturefor 2 hours. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with water and aqueous saturatedsodium chloride solution, and then dried with anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel chromatography(hexane-ethyl acetate) to obtain compound i-46 (642 mg, yield 88%).

¹H-NMR (CDCl₃) δ: 3.40 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 4.27-4.32 (m,2H), 5.03-5.07 (m, 1H), 5.08-5.12 (m, 1H), 5.15-5.21 (m, 1H), 5.25-5.33(m, 1H), 5.85-6.04 (m, 2H), 6.95 (d, J=8.0 Hz, 1H), 7.18-7.27 (m, 4H),7.30-7.37 (m, 1H), 7.88-7.94 (m, 1H).

Step 4

Compound i-46 (560 mg, 1.74 mmol) was dissolved in dichloromethane (56mL) under nitrogen atmosphere, a second generation Grubbs catalyst (147mg, 0.174 mmol) was added, and the mixture was stirred at roomtemperature for 14 hours. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gelchromatography (hexane-ethyl acetate) to obtain compound i-47 (366 mg,yield 72%).

¹H-NMR (CDCl₃) δ: 3.22-3.28 (m, 2H), 3.82 (s, 2H), 4.42-4.47 (m, 2H),5.23-5.31 (m, 1H), 5.57-5.67 (m, 1H), 6.72 (d, J=7.7 Hz, 1H), 6.95 (d,J=7.7 Hz, 1H), 7.00-7.07 (m, 2H), 7.11-7.19 (m, 1H), 7.74-7.79 (m, 1H).

Step 5

Compound i-47 (362 mg, 1.23 mmol) was dissolved in tetrahydrofuran (7mL), sodium bis(2-methoxyethoxy)aluminiumhydride-toluene solution (1.15mL, 3.69 mmol) was added dropwise under ice-cooling, and the mixture wasstirred for 45 minutes under ice-cooling. Under ice-cooling, an aqueousRochelle salt (2.11 g, 7.50 mmol) solution (30 mL) was added, and themixture was heated to room temperature. The solution was extracted withethyl acetate, and the organic layer was washed with aqueous saturatedsodium chloride solution, then dried with anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel chromatography (hexane-ethyl acetate)to obtain compound i-48 (352 mg, yield 97%).

¹H-NMR (CDCl₃) δ: 3.29-3.40 (m, 1H), 3.43-3.55 (m, 1H), 3.95 (d, J=5.5Hz, 1H), 4.06 (d, J=13.7 Hz, 1H), 4.47-4.52 (m, 2H), 4.82 (d, J=13.7 Hz,1H), 5.33-5.41 (m, 1H), 5.74-5.84 (m, 1H), 6.43 (d, J=5.8 Hz, 1H), 6.92(d, J=7.7 Hz, 1H), 6.99 (d, J=7.7 Hz, 1H), 7.06-7.14 (m, 3H), 7.46-7.52(m, 1H).

Step 6

To a tetrahydrofuran-methanol (1:1, 3 mL) solution of compound i-48 (215mg, 0.725 mmol) was added 10% palladium carbon (77.0 mg, 0.073 mmol),and the mixture was stirred at room temperature for 1.5 hours underhydrogen atmosphere. The solid was removed by filtration, and thefiltrate was distilled off under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane-ethyl acetate)to obtain compound i-49 (139 mg, yield 64%).

¹H-NMR (CDCl₃) δ: 1.45-1.55 (m, 1H), 1.67-1.80 (m, 1H), 1.85-2.01 (m,2H), 2.65-2.85 (m, 2H), 3.63-3.74 (m, 1H), 4.06-4.16 (m, 1H), 4.29 (d,J=13.5 Hz, 1H), 4.49 (d, J=13.5 Hz, 1H), 4.58-4.70 (m, 1H), 6.44 (d,J=6.9 Hz, 1H), 6.88 (d, J=7.4 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 7.07-7.11(m, 3H), 7.49-7.55 (m, 1H).

Synthesis of Intermediate Compounds i-51 and i-54

Step 1

Compound i-51 (676 mg, 2.39 mmol) was dissolved in dioxane (10 mL),dichlorobis(acetonitrile)palladium (155 mg, 0.599 mmol), sodiumcarbonate (254 mg, 2.39 mmol) and benzoquinone (259 mg, 2.39 mmol) wereadded, and the mixture was stirred in a sealed tube at 100° C. for 27hours. The mixture was diluted with ethyl acetate, and the solid wasremoved by filtration. The filtrate was washed with water and aqueoussaturated sodium chloride solution, and then dried with anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the resulting residue was purified by silica gel chromatography(hexane-ethyl acetate) to obtain compound i-51 (166 mg, yield 25%) andcompound i-52 (280 mg, yield 41%).

16: MS: m/z=280.95 [M+H]⁺.

17: ¹H-NMR (CDCl₃) δ: 1.92 (dd, J=6.6, 1.6 Hz, 3H), 4.01 (s, 2H), 6.25(dq, J=15.8, 6.6 Hz, 1H), 6.66 (d, J=7.7 Hz, 1H), 6.77 (d, J=15.8 Hz,1H), 7.30-7.51 (m, 4H), 8.26-8.31 (m, 1H), 12.67 (s, 1H).

Step 2

Compound i-52 (250 mg, 0.885 mmol) was dissolved in DMSO (2.5 mL),potassium phosphate (376 mg, 1.77 mmol) and allyl bromide (0.115 mL,1.33 mmol) were added, and the mixture was stirred at room temperaturefor 2 hours. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with water and aqueous saturatedsodium chloride solution, and then dried with anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel chromatography(hexane-ethyl acetate) to obtain compound i-53 (285 mg, yield 100%).

¹H-NMR (CDCl₃) δ: 1.88 (dd, J=6.6, 1.5 Hz, 3H), 3.98 (s, 2H), 4.31 (dt,J=5.5, 1.3 Hz, 2H), 5.17 (dd, J=10.5, 1.2 Hz, 1H), 5.29 (dq, J=17.9, 1.5Hz, 1H), 5.90-6.02 (m, 1H), 6.21 (dq, J=17.9, 6.6 Hz, 1H), 6.57 (dd,J=15.9, 1.2 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 7.17-7.24 (m, 2H),7.28-7.36 (m, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.88 (dd, J=8.2, 1.4 Hz, 1H).

Step 3

Compound i-53 (310 mg, 0.961 mmol) was dissolved in dichloromethane (31mL) under nitrogen atmosphere, a second generation Grubbs catalyst (82.0mg, 0.096 mmol) was added, and the mixture was stirred at roomtemperature for 14 hours. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gelchromatography (hexane-ethyl acetate) to obtain compound i-54 (170 mg,yield 63%).

¹H-NMR (CDCl₃) δ: 3.95 (s, 2H), 4.82 (dd, J=3.4, 1.8 Hz, 2H), 5.75 (dt,J=9.9, 3.4 Hz, 1H), 6.38 (d, J=9.9 Hz, 1H), 6.72 (d, J=7.4 Hz, 1H), 6.97(d, J=7.4 Hz, 1H), 7.19-7.26 (m, 2H), 7.30-7.38 (m, 1H), 7.95-8.00 (m,1H).

Synthesis of Intermediate Compound i-56

Step 1

Compound i-55 (100 mg, 0.328 mmol) was suspended in DMF (1 mL), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (0.124 mL, 0.983 mmol) and copperiodide (68.6 mg, 0.360 mmol) were added, and the mixture was stirred at130° C. for 4 hours. Water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with aqueous saturatedsodium chloride solution, and then dried with anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to obtaincompound i-56 (96 mg, yield 100%).

¹H-NMR (CDCl₃) δ: 4.04 (s, 2H), 7.17-7.26 (m, 2H), 7.29-7.36 (m, 1H),7.41-7.53 (m, 2H), 7.57-7.62 (m, 1H), 7.78 (d, J=7.8 Hz, 1H).

Synthesis of Intermediate Compound i-60

Step 1

Compound i-55 (3.00 g, 9.83 mmol) was suspended in DMF (30 mL), coppercyanide (2.64 g, 29.5 mmol) was added, and the mixture was refluxed for8 hours. Water was added, and the mixture was extracted with chloroform.The organic layer was washed with water, and then dried with anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and to the resulting residue were added dichloromethane-diethylether-hexane to precipitate a solid, then the solid was filtered toobtain compound i-57 (1.72 g, yield 70%).

¹H-NMR (CDCl₃) δ: 4.06 (s, 2H), 7.27-7.35 (m, 2H), 7.40-7.57 (m, 3H),7.68 (dd, J=7.4, 1.4 Hz, 1H), 8.16-8.21 (m, 1H).

Step 2

Compound i-57 (25.0 mg, 0.099 mmol) was suspended in methanol (0.5 mL),trimethylsilyl chloride (0.051 mL, 0.398 mmol) was added, and themixture was stirred at 50° C. for 4.5 hours. An aqueous sodiumbicarbonate solution was added, the mixture was extracted withchloroform, and the organic layer was dried with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel chromatography(hexane-ethyl acetate) to obtain compound i-58 (11.4 mg, yield 40%).

¹H-NMR (CDCl₃) δ: 3.87 (s, 3H), 4.09 (s, 2H), 7.25-7.53 (m, 5H),7.86-7.91 (m, 1H), 7.98 (dd, J=7.8, 1.6 Hz, 1H).

Step 3

Compound i-58 (600 mg, 2.11 mmol) was added to tetrahydrofuran (8 mL)under nitrogen atmosphere, lithium aluminum hydride (481 mg, 12.66 mmol)was added under ice-cooling, and the mixture was stirred for 45 minutesunder ice-cooling. Under ice-cooling, an aqueous saturated ammoniumchloride solution (1.5 mL) was added dropwise, and the mixture washeated to room temperature. The solution was extracted with ethylacetate, and the organic layer was washed with an aqueous hydrochloricacid solution and aqueous saturated sodium chloride solution, then driedwith anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure, and the resulting residue was purified by silica gelchromatography (hexane-ethyl acetate) to obtain compound i-59 (415 mg,yield 76%).

¹H-NMR (DMSO-d₆) δ: 3.48-3.70 (m, 1H), 4.34-4.49 (m, 2H), 4.95 (t, J=5.4Hz, 1H), 5.18-5.47 (m, 1H), 5.79-5.88 (m, 2H), 6.78-6.95 (m, 3H),6.99-7.11 (m, 3H), 7.22 (d, J=6.0 Hz, 1H).

Step 4

Compound i-59 (70.0 mg, 0.271 mmol) was suspended in acetonitrile (1mL), triethylamine (0.188 mL, 1.36 mmol), acetic acid anhydride (0.128mL, 1.36 mmol) and DMAP (16.6 mg, 0.135 mmol) were added, and themixture was stirred at room temperature for 30 minutes. Water was added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with an aqueous hydrochloric acid solution and aqueous saturatedsodium chloride solution, and then dried with anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to obtain compoundi-60 (93.0 mg, yield 100%).

¹H-NMR (CDCl₃) δ: 1.92 (s, 3H), 2.08 (s, 3H), 3.53 (d, J=14.0 Hz, 1H),5.38 (d, J=1.4 Hz, 2H), 5.47 (d, J=14.0 Hz, 1H), 7.03-7.20 (m, 4H),7.24-7.31 (m, 2H), 7.48 (dd, J=7.6, 1.2 Hz, 1H).

Synthesis of Intermediate Compound i-61

Step 1

Compound i-59 (100 mg, 0.387 mmol) was added to tetrahydrofuran undernitrogen atmosphere, sodium hydride (37.2 mg, 0.929 mmol) was addedunder ice-cooling, and the mixture was stirred for 5 minutes underice-cooling. Thereafter, methyl iodide (0.145 mL, 2.32 mmol) was added,and the mixture was stirred at room temperature for 2 hours. Water wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous hydrochloric acid solution and aqueoussaturated sodium chloride solution, and then dried with anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the resulting residue was purified by silica gel chromatography(hexane-ethyl acetate) to obtain compound i-61 (106 mg, yield 96%).

¹H-NMR (CDCl₃) δ: 3.29 (s, 3H), 3.34 (s, 3H), 3.40 (d, J=13.1 Hz, 1H),4.45-4.58 (m, 2H), 5.63 (s, 1H), 5.70 (d, J=13.1 Hz, 1H), 7.00-7.24 (m,6H), 7.35 (d, J=7.4 Hz, 1H).

Synthesis of Intermediate Compound i-65

Step 1

Compound i-55 (2.10 g, 6.88 mmol) was suspended in DMF (10.5 mL), copperiodide (262 mg, 1.38 mmol), dichlorobis(triphenylphosphine)palladium(966 mg, 1.38 mmol), trimethylsilylacetylene (4.86 mL, 34.4 mmol), andtriethylamine (14.0 mL, 101 mmol) were added, and the mixture wasstirred in a sealed tube at 140° C. for 11 hours. The mixture wasdiluted with ethyl acetate, and the solid was removed by filtration. Thefiltrate was washed with an aqueous hydrochloric acid solution andaqueous saturated sodium chloride solution, and then dried withanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gelchromatography (hexane-ethyl acetate) to obtain compound i-62 (1.34 g,yield 60%).

MS: m/z=323.05 [M+H]⁺.

Step 2

Compound i-62 (1.34 g, 4.16 mmol) was dissolved in methanol (40 mL),potassium carbonate (1.72 g, 12.5 mmol) was added, and the mixture wasstirred at room temperature for 1.5 hours. Water was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith aqueous saturated sodium chloride solution, and then dried withanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gelchromatography (hexane-ethyl acetate) to obtain compound i-63 (967 mg,yield 93%).

¹H-NMR (CDCl₃) δ: 3.20 (s, 1H), 4.05 (s, 2H), 7.14-7.30 (m, 4H), 7.40(t, J=7.8 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.79 (dt, J=7.7, 0.8 Hz, 1H).

Step 3

Compound i-63 (619 mg, 2.47 mmol) was added to tetrahydrofuran (12 mL)under nitrogen atmosphere, lithium aluminum hydride (282 mg, 7.42 mmol)was added under ice-cooling, and the mixture was stirred for 1 hourunder ice-cooling. Under ice-cooling, an aqueous saturated ammoniumchloride solution (15 mL) was added dropwise, and the mixture was heatedto room temperature. The solution was extracted with ethyl acetate, andthe organic layer was washed with an aqueous hydrochloric acid solutionand aqueous saturated sodium chloride solution, then dried withanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gelchromatography (hexane-ethyl acetate) to obtain compound i-64 (554 mg,yield 89%).

¹H-NMR (CDCl₃) δ: 2.73 (d, J=3.4 Hz, 1H), 3.41 (s, 1H), 3.57 (d, J=13.6Hz, 1H), 5.63 (d, J=13.6 Hz, 1H), 6.55 (d, J=3.4 Hz, 1H), 7.04-7.26 (m,5H), 7.37-7.44 (m, 2H).

Step 4

A tetrahydrofuran (2 mL) solution of compound i-64 (50.0 mg, 0.198 mmol)was cooled to −78° C. with dry ice-acetone under nitrogen atmosphere. A1.65 mol/L n-butyllithium-hexane solution (0.312 mL, 0.515 mmol) wasadded dropwise thereto, and the mixture was stirred at room temperaturefor 20 minutes. The mixture was again cooled to −78° C. with dryice-acetone, then methyl iodide (0.248 mL, 3.96 mmol) was addeddropwise, and the mixture was stirred for 1.5 hours while the mixturewas heated to room temperature. An aqueous saturated ammonium chloridesolution (1.5 mL) was added, and the mixture was extracted with ethylacetate. The organic layer was washed with water and aqueous saturatedsodium chloride solution, and then dried with anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel column chromatography(hexane-ethyl acetate) to obtain compound i-65 (44.9 mg, yield 81%).

¹H-NMR (CDCl₃) δ: 2.14 (s, 3H), 3.34 (s, 3H), 3.38 (d, J=13.5 Hz, 1H),5.62 (d, J=13.5 Hz, 1H), 5.97 (s, 1H), 7.01-7.23 (m, 5H), 7.29 (dd,J=7.3, 1.8 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H).

Synthesis of Intermediate Compound i-67

Step 1

To a tetrahydrofuran-methanol (1:1, 6 mL) solution of compound i-66 (520mg, 1.92 mmol) was added 10% palladium carbon (205 mg, 0.192 mmol), andthe mixture was stirred at room temperature for 1 hour under hydrogenatmosphere. The solid was removed by filtration, and the filtrate wasdistilled off under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (hexane-ethyl acetate) to obtaincompound i-67 (370 mg, yield 70%).

¹H-NMR (CDCl₃) δ: 1.25 (t, J=7.5 Hz, 3H), 2.48 (d, J=1.7 Hz, 1H), 2.82(dq, J=2.7, 7.5 Hz, 2H), 3.63 (d, J=13.6 Hz, 1H), 5.79 (d, J=13.6 Hz,1H), 6.25 (s, 1H), 6.97-7.32 (m, 7H).

Synthesis of Intermediate Compound i-69

Step 1

A tetrahydrofuran (40 mL) solution of compound i-68 (1.00 g, 3.81 mmol)was cooled to −78° C. with dry ice-acetone under nitrogen atmosphere. A1.65 mol/L n-butyllithium-hexane solution (6.92 mL, 11.4 mmol) was addeddropwise thereto, and the mixture was stirred at room temperature for 30minutes. The mixture was again cooled to −78° C. with dry ice-acetone,then methyl iodide (2.38 mL, 38.1 mmol) was added dropwise, and themixture was stirred for 2.5 hours while the mixture was heated to roomtemperature. After the reaction solution was concentrated, water wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with aqueous saturated sodium chloride solution, andthen dried with anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and the resulting residue was purified bysilica gel column chromatography (hexane-ethyl acetate) to obtaincompound i-69 (522 mg, yield 50%).

¹H-NMR (CDCl₃) δ: 1.74 (d, J=6.9 Hz, 3H), 4.96-5.09 (m, 2H), 6.65 (d,J=10.7 Hz, 1H), 7.10-7.28 (m, 6H), 7.49-7.52 (m, 1H).

Synthesis of Intermediate Compound i-72

Step 1

Compound i-70 (500 mg, 1.36 mmol) was dissolved in dichloromethane (10mL), Boc₂O (0.348 mL, 1.50 mmol) and DMAP (16 mg, 0.136 mmol) wereadded, and the mixture was stirred at room temperature for 1 hour.Thereafter, NCS (273 mg, 2.04 mmol) was added, and the mixture washeated to reflux for 7 hours, and then stirred at room temperature for 4days.

The reaction solution was concentrated, and the resulting residue waspurified by silica gel column chromatography (chloroform-methanol) toobtain compound i-71 (670 mg, yield 98%).

MS: m/z=502.12 [M+H]⁺

Step 2

To an ethanol solution of compound i-71 (670 mg, 1.34 mmol) was added a2M aqueous hydrochloric acid solution (3.34 mL, 6.67 mmol), and themixture was stirred at 60° C. for 3 hours. Saturated sodium bicarbonatewater was added, the mixture was extracted with chloroform. The organiclayer was washed with water and aqueous saturated sodium chloridesolution, and then dried with anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure to obtain compound i-72 (452mg, 1.13 mmol).

MS: m/z=402.08 [M+H]⁺

Hereinbelow, Reference examples 666 to 775 were synthesized using theabove intermediate compounds.

Synthesis of Reference Example 666

First Step

Compound 666A (1.0 g, 2.4 mmol),10-chloro-6,11-dihydrodibenzo[b,e]thiepin-11-ol (741 mg, 2.8 mmol), anda propanephosphonic acid anhydride-50% ethyl acetate solution (10 mL,16.8 mmol) were mixed, and the mixture was stirred at 100° C. for 5hours. To the reaction solution was added ethyl acetate, the solutionwas diluted, and the solution was washed with water and aqueoussaturated sodium chloride solution, and then dried with anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel chromatography(hexane-ethyl acetate) to obtain compound 666B (451 mg, yield 29%).

¹H-NMR (CDCl₃) δ: 1.09 (d, J=7.5 Hz, 3H), 3.62 (d, J=13.5 Hz, 1H), 3.76(s, 3H), 4.37 (d, J=13.2 Hz, 1H), 4.80 (d, J=13.2 Hz, 1H), 5.43 (d, 10.5Hz, 1H), 5.53-5.66 (m, 3H), 5.86 (s, 1H), 6.58 (m, 1H), 6.76 (m, 1H),7.04-7.13 (m, 2H), 7.26-7.38 (m, 6H), 7.58-7.63 (m, 2H), 7.99 (s, 1H).

Second Step

Compound 666B (570 mg, 0.85 mmol) was dissolved in tetrahydrofuran (6mL) and methanol (1.5 mL). The solution was ice-cooled, a 2 mol/Laqueous sodium hydroxide solution (0.64 mL, 1.28 mmol) was addedthereto, and the mixture was stirred at 0° C. for 30 minutes.Hydrochloric acid was added to the reaction solution to stop thereaction, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and aqueous saturated sodium chloridesolution, and then dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting residue waspurified by silica gel chromatography (hexane-ethyl acetate) to obtaincompound 666C (433 mg, yield 78%).

¹H-NMR (CDCl₃) δ: 1.09 (d, J=7.2 Hz, 3H), 3.62 (d, J=13.8 Hz, 1H), 4.42(d, J=13.2 Hz, 1H), 4.82 (d, J=13.2 Hz, 1H), 5.50-5.62 (m, 3H), 5.66 (d,J=10.8 Hz, 1H), 5.82 (s, 1H), 6.38 (m, 1H), 6.70 (m, 1H), 7.05-7.16 (m,2H), 7.26-7.39 (m, 6H), 7.51-7.56 (m, 2H), 8.12 (s, 1H), 14.31 (s, 1H).

Third Step

Compound 666C (289 mg, 0.44 mmol) was dissolved in tetrahydrofuran (5mL). The solution was ice-cooled, triethylamine (0.18 mL, 1.3 mmol) andethyl chloroformate (0.11 mL, 1.1 mmol) were added, and the mixture wasstirred for 15 minutes. The mixture was cooled to −78° C. with dryice-acetone, a DIBAL-hexane solution (2.1 mL, 2.2 mmol) was added, andthe mixture was stirred at −78° C. for 40 minutes. To the reactionsolution was added ethyl acetate to stop the reaction, and the mixturewas heated to room temperature. An aqueous potassium sodium tartratesolution was added, and the mixture was stirred vigorously at roomtemperature for 2 hours. The organic layer was dried with anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the resulting residue was dissolved in DMF (2 ml). Lithium chloride(70 mg, 1.7 mmol) was added, and the mixture was stirred at 100° C. for2 hours. The mixture was allowed to cool, diluted with ethyl acetate,and washed with 2 mol/L hydrochloric acid, water, and aqueous saturatedsodium chloride solution. The solvent was distilled off under reducedpressure, and to the resulting residue were added ethylacetate-diisopropyl ether to precipitate a solid, then the solid wasfiltered to obtain compound 666 (40.5 mg, yield 17%).

¹H-NMR (CDCl₃) δ: 1.16 (d, J=7.2 Hz, 3H), 3.63 (d, J=13.5 Hz, 1H), 4.06(d, J=13.2 Hz, 1H), 4.24 (d, J=13.2 Hz, 1H), 4.44 (d, J=12.9 Hz, 1H),4.87 (d, J=12.9 Hz, 1H), 5.50 (m, 1H), 5.72 (d, J=13.5 Hz, 1H), 5.93 (s,1H), 6.75 (m, 1H), 6.83 (m, 1H), 7.09-7.14 (m, 2H), 7.22 (s, 1H),7.27-7.39 (m, 1H).

MS: m/z=552.2 [M+H]⁺.

Reference Example 667

MS: m/z=480.15 [M+H]⁺.

Reference Example 668

MS: m/z=524 [M+H]⁺.

Reference Example 669

MS: m/z=524 [M+H]⁺.

Reference Example 670

MS: m/z=520 [M+H]⁺.

Reference Example 671

MS: m/z=520 [M+H]⁺.

Reference Examples 672

MS: m/z=520 [M+H]⁺.

Reference Example 673

MS: m/z=522.19 [M+H]⁺.

Reference Example 674

MS: m/z=566.98 [M+H]⁺.

Reference Example 675

MS: m/z=532.22 [M+H]⁺.

Reference Example 676

MS: m/z=532.22 [M+H]⁺.

Reference Example 677

MS: m/z=488 [M+H]⁺. RT=2.11 min.

Reference Example 678

MS: m/z=542 [M+H]⁺. RT=2.23 min.

Reference Example 679

MS: m/z=506 [M+H]⁺. RT=2.21 min.

Reference Example 680

MS: m/z=534 [M+H]⁺. RT=2.06 min.

Reference Example 681

MS: m/z=500 [M+H]⁺. RT=2.05 min.

Reference Example 682

MS: m/z=482 [M+H]⁺. RT=1.76 min.

Reference Example 683

MS: m/z=600 [M+H]⁺. RT=2.32 min. (

6

)

Reference Example 684

MS: m/z=482 [M+H]⁺. RT=1.82 min.

Reference Example 685

MS: m/z=564 [M+H]⁺. RT=2.23 min.

Reference Example 686

MS: m/z=[M+H]⁺. RT=. min.

Reference Example 687

MS: m/z=547 [M+H]⁺. RT=2.20 min.

Reference Example 688

MS: m/z=565 [M+H]⁺. RT=2.03 min.

Reference Example 689

MS: m/z=486 [M+H]⁺. RT=1.96 min.

Reference Example 690

MS: m/z=486 [M+H]⁺. RT=1.96 min.

Reference Example 691

MS: m/z=529 [M+H]⁺. RT=2.21 min.

Reference Example 692

MS: m/z=566 [M+H]⁺. RT=2.23 min.

Reference Example 693

MS: m/z=566 [M+H]⁺. RT=2.16 min.

Reference Example 694

MS: m/z=564 [M+H]⁺. RT=2.33 min.

Reference Example 695

MS: m/z=548 [M+H]⁺. RT=2.20 min.

Reference Example 696

MS: m/z=548 [M+H]⁺. RT=2.17 min.

Reference Example 697

MS: m/z=558 [M+H]⁺. RT=2.31 min.

Reference Example 698

MS: m/z=578 [M+H]⁺. RT=2.35 min.

Reference Example 699

MS: m/z=598 [M+H]⁺. RT=2.37 min.

Reference Example 700

MS: m/z=532 [M+H]⁺. RT=2.02 min.

Reference Example 701

MS: m/z=536 [M+H]⁺. RT=2.14 min.

Reference Example 702

MS: m/z=570 [M+H]⁺. RT=2.35 min.

Reference Example 703

MS: m/z=520 [M+H]⁺. RT=2.13 min.

Reference Example 704

MS: m/z=538 [M+H]⁺. RT=2.24 min.

Reference Example 705

MS: m/z=502 [M+H]⁺. RT=2.13 min.

Reference Example 706

MS: m/z=566 [M+H]⁺. RT=2.27 min.

Reference Example 707

MS: m/z=566 [M+H]⁺. RT=2.11 min.

Reference Example 708

MS: m/z=550 [M+H]⁺. RT=2.06 min.

Reference Example 709

MS: m/z=568 [M+H]⁺. RT=2.14 min.

Reference Example 710

MS: m/z=566 [M+H]⁺. RT=2.00 min.

Reference Example 711

¹H-NMR (CDCl₃) δ: 1.23 (d, J=7.5 Hz, 3H), 4.11 (d, J=13.8 Hz, 1H), 4.48(d, J=12.9 Hz, 1H), 4.90 (d, J=12.9 Hz, 1H), 5.13 (s, 1H), 5.41 (dd,J=13.8, 3.0 Hz, 1H), 5.54 (m, 1H), 5.82 (d, J=7.8 Hz, 1H), 6.69 (d,J=7.2 Hz, 1H), 6.85 (m, 1H), 6.96 (m, 1H), 7.03-7.14 (m, 3H), 7.16 (d,J=7.2 Hz, 1H).

Reference Example 712

¹H-NMR (CDCl₃) δ: 1.19 (d, J=6.9 Hz, 3H), 3.61 (d, J=13.5 Hz, 1H), 4.07(d, J=13.2 Hz, 1H), 4.24 (d, J=13.2 Hz, 1H), 4.50 (d, J=13.2 Hz, 1H),4.88 (d, J=13.2 Hz, 1H), 5.09 (s, 1H), 5.51 (m, 1H), 5.67 (d, J=13.5 Hz,1H), 6.66 (m, 1H), 6.79 (m, 1H), 7.04-7.12 (m, 2H), 7.18 (m, 1H),7.24-7.30 (m, 2H), 7.35-7.46 (m, 2H).

MS: m/z=518.3 [M+H]⁺.

Reference Example 713

¹H-NMR (CDCl₃) δ: 1.25 (d, J=7.2 Hz, 3H), 4.07 (d, J=13.2 Hz, 1H), 4.10(d, J=13.8 Hz, 1H), 4.29 (d, J=13.2 Hz, 1H), 4.48 (d, J=13.2 Hz, 1H),4.90 (d, J=13.2 Hz, 1H), 5.12 (s, 1H), 5.44 (dd, J=13.8, 3.0 Hz, 1H),5.52 (m, 1H), 6.64 (m, 1H), 6.82 (m, 1H), 6.95 (m, 1H), 7.02-7.13 (m,3H), 7.25 (s, 1H).

MS: m/z=554.2 [M+H]⁺.

Reference Example 714

¹H-NMR (CDCl₃) δ: 2.98 (m, 1H), 3.46 (m, 1H), 3.57 (t, J=10.5 Hz, 1H),3.58 (d, J=13.5 Hz, 1H), 3.79 (dd, J=12.3, 3.0 Hz, 1H), 3.96 (dd,J=11.4, 3.0 Hz, 1H), 4.63 (m, 2H), 5.25 (s, 1H), 5.52 (d, J=13.5 Hz,1H), 5.75 (d, J=7.8 Hz, 1H), 6.70 (m, 1H), 6.81 (m, 1H), 7.04-7.10 (m,3H), 7.19-7.37 (m, 3H), 7.43 (m, 1H).

MS: m/z=448.1 [M+H]⁺.

Reference Example 715

¹H-NMR (CDCl₃) δ: 2.83 (m, 1H), 3.43 (m, 1H), 3.55 (t, J=10.5 Hz, 1H),3.61 (d, J=13.8 Hz, 1H), 3.78 (dd, J=12.0, 3.0 Hz, 1H), 4.04 (dd,J=11.1, 3.0 Hz, 1H), 4.50 (m, 1H), 4.60 (m, 1H), 5.13 (s, 1H), 5.64 (d,J=13.8 Hz, 1H), 5.73 (d, J=7.8 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.81 (m,1H), 7.07-7.15 (m, 2H), 7.20-7.37 (m, 5H).

MS: m/z=448.1 [M+H]⁺.

Reference Example 716

¹H-NMR (CDCl₃) δ: 1.26 (d, J=7.2 Hz, 3H), 4.13 (d, J=13.8 Hz, 1H), 4.49(d, J=13.2 Hz, 1H), 4.94 (d, J=13.2 Hz, 1H), 5.13 (s, 1H), 5.38 (dd,J=13.8, 2.4 Hz, 1H), 5.52 (m, 1H), 6.68 (m, 1H), 6.86 (m, 1H), 6.97 (m,1H), 7.03-7.20 (m, 3H), 7.50 (s, 1H).

MS: m/z=558.0 [M+H]⁺.

Reference Example 717

¹H-NMR (CDCl₃) δ: 1.18 (d, J=7.2 Hz, 3H), 3.65 (d, J=13.5 Hz, 1H), 4.47(d, J=12.9 Hz, 1H), 4.90 (d, J=12.9 Hz, 1H), 5.49 (m, 1H), 5.66 (d,J=13.5 Hz, 1H), 5.93 (s, 1H), 6.60 (t, J=54.9 Hz, 1H), 6.77 (m, 1H),6.86 (m, 1H), 7.11-7.16 (m, 2H), 7.28-7.37 (m, 3H), 7.49 (s, 1H).

Reference Example 718

¹H-NMR (CDCl₃) δ: 1.25 (d, J=7.2 Hz, 3H), 4.11 (d, J=13.8 Hz, 1H), 4.51(d, J=13.2 Hz, 1H), 4.93 (d, J=13.2 Hz, 1H), 5.11 (s, 1H), 5.38 (dd,J=13.8, 3.0 Hz, 1H), 5.52 (m, 1H), 6.58 (t, J=54.6 Hz, 1H), 6.65 (m,1H), 6.84 (m, 1H), 6.95 (m, 1H), 7.02-7.15 (m, 3H), 7.52 (s, 1H).

Reference Example 719

¹H-NMR (CDCl₃) δ: 1.23 (d, J=7.2 Hz, 3H), 4.08 (d, J=12.9 Hz, 1H), 4.24(d, J=13.5 Hz, 1H), 4.32 (d, J=14.1 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H),4.90 (d, J=13.5 Hz, 1H), 5.13 (s, 1H), 5.53 (m, 1H), 5.64 (d, J=14.1 Hz,1H), 6.64 (m, 1H), 6.80 (m, 1H), 7.06-7.12 (m, 3H), 7.20 (m, 1H), 7.24(s, 1H), 7.53 (m, 1H).

MS: m/z=552.2 [M+H]⁺.

Reference Example 720

¹H-NMR (CDCl₃) δ: 0.90 (d, J=7.4 Hz, 3H), 2.25 (s, 3H), 2.34 (s, 3H),3.70 (d, J=13.5 Hz, 1H), 4.49 (d, J=12.9 Hz, 1H), 4.81 (d, J=12.9 Hz,1H), 5.38-5.50 (m, 2H), 5.62 (d, J=13.5 Hz, 1H), 5.84 (d, J=7.7 Hz, 1H),6.56 (d, J=7.7 Hz, 1H), 6.75 (t, J=7.6 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H),7.05 (d, J=7.7 Hz, 1H), 7.12 (d, J=7.1 Hz, 1H), 7.21 (d, J=6.6 Hz, 1H),7.26-7.32 (m, 1H).

Reference Example 721

¹H-NMR (CDCl₃) δ: 0.93 (d, J=7.2 Hz, 3H), 2.38 (s, 3H), 3.75 (d, J=13.6Hz, 1H), 4.52 (d, J=12.9 Hz, 1H), 4.85 (d, J=12.9 Hz, 1H), 5.41-5.54 (m,2H), 5.69 (d, J=13.6 Hz, 1H), 5.93 (d, J=7.7 Hz, 1H), 6.68 (d, J=7.6 Hz,1H), 6.84 (t, J=7.8 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 7.18 (d, J=7.6 Hz,1H), 7.25-7.40 (m, 3H).

Reference Example 722

¹H-NMR (CDCl₃) δ: 0.90 (d, J=7.4 Hz, 3H), 2.34 (s, 3H), 3.69 (d, J=13.5Hz, 1H), 4.48 (d, J=12.6 Hz, 1H), 4.82 (d, J=12.6 Hz, 1H), 5.38-5.50 (m,2H), 5.62 (d, J=13.5 Hz, 1H), 5.88 (d, J=7.7 Hz, 1H), 6.53 (d, J=7.7 Hz,1H), 6.83 (td, J=8.0, 5.5 Hz, 1H), 6.92-7.00 (m, 1H), 7.03 (d, J=7.7 Hz,1H), 7.15 (d, J=7.4 Hz, 1H), 7.23 (d, J=7.1 Hz, 1H), 7.32 (t, J=7.6 Hz,1H).

Reference Example 723

¹H-NMR (CDCl₃) δ: 1.19 (d, J=7.4 Hz, 3H), 2.24 (s, 3H), 4.09 (d, J=14.3Hz, 1H), 4.44 (d, J=12.9 Hz, 1H), 4.91 (d, J=12.9 Hz, 1H), 5.27 (s, 1H),5.49-5.59 (m, 1H), 5.81 (d, J=7.7 Hz, 1H), 5.91 (d, J=14.3 Hz, 1H), 6.58(d, J=7.7 Hz, 1H), 6.76 (t, J=7.6 Hz, 1H), 7.02-7.10 (m, 2H), 7.34-7.43(m, 2H), 7.70-7.83 (m, 1H).

Reference Example 724

¹H-NMR (CDCl₃) δ: 0.89 (d, J=7.2 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H),2.62-2.77 (m, 2H), 3.68 (d, J=13.6 Hz, 1H), 4.44 (d, J=12.7 Hz, 1H),4.79 (d, J=12.7 Hz, 1H), 5.37-5.47 (m, 1H), 5.58 (s, 1H), 5.69 (d,J=13.6 Hz, 1H), 5.87 (d, J=7.6 Hz, 1H), 6.53 (d, J=7.3 Hz, 1H), 6.82(td, J=7.8, 5.8 Hz, 1H), 6.90-6.98 (m, 1H), 7.00 (d, J=7.6 Hz, 1H),7.17-7.23 (m, 2H), 7.36 (t, J=7.5 Hz, 1H).

Reference Example 725

MS: m/z=534.20 [M+H]⁺.

Reference Example 726

¹H-NMR (CDCl₃) δ: 1.15 (d, J=7.4 Hz, 3H), 3.55 (s, 1H), 3.71 (d, J=13.5Hz, 1H), 4.44 (d, J=12.9 Hz, 1H), 4.87 (d, J=12.9 Hz, 1H), 5.43-5.54 (m,1H), 5.65 (d, J=13.5 Hz, 1H), 5.87 (d, J=7.7 Hz, 1H), 6.14 (s, 1H), 6.63(d, J=7.4 Hz, 1H), 6.84 (td, J=8.0, 5.7 Hz, 1H), 6.91-7.00 (m, 1H), 7.10(d, J=7.7 Hz, 1H), 7.37-7.42 (m, 2H), 7.46-7.52 (m, 1H).

Reference Example 727

MS: m/z=530.10 [M+H]⁺.

Reference Example 728

¹H-NMR (CDCl₃) δ: 1.09 (d, J=7.1 Hz, 3H), 3.59 (d, J=13.5 Hz, 1H), 3.79(s, 3H), 4.51 (d, J=12.9 Hz, 1H), 4.84 (d, J=12.9 Hz, 1H), 5.43-5.56 (m,1H), 5.67 (d, J=13.5 Hz, 1H), 5.83 (d, J=7.7 Hz, 1H), 5.92 (s, 1H), 6.74(d, J=7.7 Hz, 1H), 6.77-6.86 (m, 2H), 6.95 (d, J=7.7 Hz, 1H), 7.05-7.10(m, 2H), 7.19 (d, J=7.7 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H).

Reference Example 729

MS: m/z=512.10 [M+H]⁺.

Reference Example 730

¹H-NMR (CDCl₃) δ: 1.18 (d, J=7.1 Hz, 3H), 3.55 (s, 1H), 3.63 (d, J=13.2Hz, 1H), 4.46 (d, J=11.5 Hz, 1H), 4.94 (d, J=11.5 Hz, 1H), 5.44-5.54 (m,1H), 5.63 (d, J=13.2 Hz, 1H), 6.01 (d, J=4.4 Hz, 1H), 6.07 (s, 1H), 6.77(d, J=7.4 Hz, 1H), 6.83-6.85 (m, 1H), 7.07-7.16 (m, 2H), 7.17-7.24 (m,1H), 7.36-7.40 (m, 2H), 7.44-7.50 (m, 1H).

Reference Example 731

¹H-NMR (CDCl₃) δ: 0.91 (d, J=7.4 Hz, 3H), 1.08 (t, J=7.4 Hz, 3H),2.62-2.79 (m, 2H), 3.59 (d, J=13.2 Hz, 1H), 4.46 (d, J=12.6 Hz, 1H),4.82 (d, J=12.6 Hz, 1H), 5.38-5.48 (m, 1H), 5.51 (s, 1H), 5.68 (d,J=13.2 Hz, 1H), 5.92 (d, J=6.9 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H),6.78-6.87 (m, 1H), 7.05 (d, J=7.1 Hz, 1H), 7.09-7.14 (m, 2H), 7.19 (d,J=7.7 Hz, 1H), 7.23 (d, J=7.4 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H).

Reference Example 732

MS: m/z=516.75 [M+H]⁺.

Reference Example 733

¹H-NMR (CDCl₃) δ: 0.23 (d, J=7.1 Hz, 3H), 3.75 (d, J=13.5 Hz, 1H), 4.47(d, J=12.9 Hz, 1H), 4.84 (d, J=12.9 Hz, 1H), 5.23-5.33 (m, 1H), 5.91 (d,J=7.7 Hz, 1H), 5.97 (d, J=13.5 Hz, 1H), 6.19 (s, 1H), 6.81-6.93 (m, 2H),7.07-7.12 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.52(d, J=7.4 Hz, 1H), 7.57-7.64 (m, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.92 (d,J=8.5 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H).

Reference Example 734

¹H-NMR (CDCl₃) δ: 1.12 (d, J=5.8 Hz, 6H), 1.43 (d, J=6.0 Hz, 3H), 3.58(d, J=13.5 Hz, 1H), 4.43-4.57 (m, 2H), 4.84 (d, J=12.9 Hz, 1H),5.41-5.52 (m, 1H), 5.61 (d, J=13.5 Hz, 1H), 5.88 (d, J=7.7 Hz, 1H), 5.94(s, 1H), 6.67 (d, J=7.7 Hz, 1H), 6.77-6.87 (m, 2H), 6.91 (d, J=7.1 Hz,1H), 7.09 (d, J=3.6 Hz, 2H), 7.16 (d, J=7.7 Hz, 1H), 7.31 (t, J=8.0 Hz,1H).

Reference Example 735

¹H-NMR (DMSO-d₆) δ: 0.93 (d, J=7.4 Hz, 3H), 3.59 (d, J=13.5 Hz, 1H),4.27 (d, J=12.9 Hz, 1H), 4.84 (d, J=12.9 Hz, 1H), 5.24-5.35 (m, 1H),5.38 (d, J=13.5 Hz, 1H), 5.48 (d, J=7.4 Hz, 1H), 5.59 (s, 1H), 6.50 (d,J=7.4 Hz, 1H), 6.57-6.71 (m, 4H), 6.86-7.03 (m, 5H), 9.98 (s, 1H).

Reference Example 736

¹H-NMR (CDCl₃) δ: 1.00-1.10 (m, 6H), 1.74-1.87 (m, 2H), 3.59 (d, J=13.2Hz, 1H), 3.78-3.95 (m, 2H), 4.55 (d, J=12.4 Hz, 1H), 4.92 (d, J=12.4 Hz,1H), 5.39-5.52 (m, 1H), 5.65 (d, J=13.2 Hz, 1H), 5.97 (s, 1H), 6.01-6.11(m, 1H), 6.66 (d, J=7.4 Hz, 1H), 6.81 (d, J=8.2 Hz, 2H), 6.93 (d, J=7.4Hz, 1H), 7.07-7.11 (m, 2H), 7.21-7.25 (m, 1H), 7.32 (t, J=8.0 Hz, 1H).

Reference Example 737

¹H-NMR (CDCl₃) δ: 1.09 (d, J=7.1 Hz, 3H), 1.40 (t, J=6.9 Hz, 3H), 3.59(d, J=13.2 Hz, 1H), 3.87-4.07 (m, 2H), 4.53 (d, J=13.2 Hz, 1H), 4.86 (d,J=13.2 Hz, 1H), 5.43-5.53 (m, 1H), 5.64 (d, J=13.2 Hz, 1H), 5.91 (d,J=7.4 Hz, 1H), 5.96 (s, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.78-6.84 (m, 2H),6.93 (d, J=7.4 Hz, 1H), 7.06-7.10 (m, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.32(t, J=8.0 Hz, 1H).

Reference Example 738

MS: m/z=532.5 [M+H]⁺.

Reference Example 739

¹H-NMR (CDCl₃) δ: 0.93 (d, J=6.9 Hz, 3H), 3.73 (d, J=13.7 Hz, 1H), 4.58(d, J=12.9 Hz, 1H), 4.64 (d, J=11.8 Hz, 1H), 4.82-4.90 (m, 2H),5.31-5.43 (m, 1H), 5.62 (d, J=13.7 Hz, 1H), 5.90 (d, J=7.7 Hz, 1H), 6.09(s, 1H), 6.65 (d, J=6.6 Hz, 1H), 6.69-6.78 (m, 1H), 6.90-6.98 (m, 1H),7.00 (d, J=7.7 Hz, 1H), 7.27-7.41 (m, 3H).

Reference Example 740

¹H-NMR (CDCl₃) δ: 1.16 (d, J=7.1 Hz, 3H), 3.49 (s, 1H), 3.60 (d, J=13.2Hz, 1H), 4.49-4.62 (m, 2H), 4.74 (dd, J=15.9, 2.2 Hz, 1H), 4.85 (d,J=13.5 Hz, 1H), 5.44-5.57 (m, 1H), 5.67 (d, J=13.2 Hz, 1H), 5.82 (d,J=7.7 Hz, 1H), 5.89 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.78-6.85 (m, 1H),7.01 (dd, J=8.1, 3.7 Hz, 2H), 7.05-7.12 (m, 2H), 7.20 (d, J=7.7 Hz, 1H),7.36 (t, J=8.1 Hz, 1H).

Reference Example 741

MS: m/z=556.15 [M+H]⁺.

Reference Example 742

MS: m/z=556.15 [M+H]⁺.

Reference Example 743

¹H-NMR (CDCl₃) δ: 1.15 (d, J=7.4 Hz, 3H), 2.14 (s, 3H), 3.59 (d, J=13.5Hz, 1H), 4.45 (d, J=12.9 Hz, 1H), 4.85 (d, J=12.9 Hz, 1H), 5.43-5.53 (m,1H), 5.58 (d, J=13.5 Hz, 1H), 5.83 (d, J=7.7 Hz, 1H), 6.08 (s, 1H), 6.71(d, J=7.4 Hz, 1H), 6.80-6.87 (m, 1H), 7.07-7.14 (m, 3H), 7.26-7.38 (m,3H).

Reference Example 744

¹H-NMR (CDCl₃) δ: 1.16 (d, J=7.1 Hz, 3H), 1.78 (d, J=6.9 Hz, 3H), 2.14(s, 3H), 4.43 (d, J=12.9 Hz, 1H), 4.83 (d, J=12.9 Hz, 1H), 5.42-5.54 (m,1H), 5.84 (d, J=7.7 Hz, 1H), 5.99 (q, J=7.1 Hz, 1H), 6.22 (s, 1H), 6.69(d, J=7.1 Hz, 1H), 6.79-6.86 (m, 1H), 7.03-7.14 (m, 3H), 7.31-7.42 (m,3H).

Reference Example 745

¹H-NMR (CDCl₃) δ: 1.03 (d, J=6.7 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H), 1.78(d, J=6.4 Hz, 3H), 4.34 (d, J=12.3 Hz, 1H), 4.70-4.84 (m, 1H), 5.03 (d,J=12.3 Hz, 1H), 6.08-6.27 (m, 3H), 6.70-6.86 (m, 2H), 7.01-7.22 (m, 3H),7.30-7.42 (m, 3H).

Reference Example 746

¹H-NMR (CDCl₃) δ: 0.88 (d, J=7.1 Hz, 3H), 3.43 (s, 3H), 3.62 (d, J=13.5Hz, 1H), 4.27 (d, J=11.0 Hz, 1H), 4.38 (d, J=11.0 Hz, 1H), 4.52 (d,J=13.2 Hz, 1H), 4.84 (d, J=13.2 Hz, 1H), 5.25-5.35 (m, 1H), 5.60 (d,J=13.5 Hz, 1H), 5.70 (s, 1H), 5.91 (d, J=7.1 Hz, 1H), 6.64 (d, J=7.4 Hz,1H), 6.80-6.88 (m, 1H), 6.96 (d, J=7.7 Hz, 1H), 7.10-7.16 (m, 2H), 7.22(dd, J=6.3, 2.5 Hz, 1H), 7.32-7.39 (m, 2H).

Reference Example 747

MS: m/z=532.20 [M+H]⁺.

Reference Example 748

¹H-NMR (CDCl₃) δ: 1.15 (d, J=7.4 Hz, 3H), 1.80 (d, J=6.9 Hz, 3H), 4.42(d, J=13.2 Hz, 1H), 4.86 (d, J=13.2 Hz, 1H), 5.46-5.57 (m, 1H), 5.83 (d,J=7.7 Hz, 1H), 6.07 (s, 1H), 6.12 (q, J=7.1 Hz, 1H), 6.77-6.89 (m, 2H),7.04-7.17 (m, 3H), 7.33-7.45 (m, 3H).

Reference Example 749

MS: m/z=536.05 [M+H]⁺.

Reference Example 750

¹H-NMR (CDCl₃) δ: 0.96 (d, J=7.4 Hz, 3H), 3.64 (d, J=13.7 Hz, 1H), 4.58(d, J=13.2 Hz, 1H), 4.64 (d, J=11.8 Hz, 1H), 4.82-4.91 (m, 2H),5.33-5.43 (m, 1H), 5.60 (d, J=13.7 Hz, 1H), 5.86 (d, J=7.4 Hz, 1H), 6.01(s, 1H), 6.71-6.83 (m, 2H), 7.02 (d, J=7.7 Hz, 1H), 7.11 (d, J=3.6 Hz,2H), 7.27-7.39 (m, 3H).

Reference Example 751

MS: m/z=557.20 [M+H]⁺.

Reference Example 752

¹H-NMR (CDCl₃) δ: 1.05 (d, J=7.1 Hz, 3H), 2.49 (s, 6H), 3.50 (d, J=13.7Hz, 1H), 4.24 (d, J=13.2 Hz, 1H), 4.72 (d, J=13.2 Hz, 1H), 5.35-5.48 (m,1H), 5.80 (d, J=8.0 Hz, 1H), 5.91 (d, J=13.7 Hz, 1H), 6.05 (s, 1H),6.75-6.86 (m, 2H), 7.02-7.15 (m, 5H), 7.36 (t, J=7.8 Hz, 1H).

Reference Example 753

MS: m/z=531.25 [M+H]⁺.

Reference Example 754

¹H-NMR (CDCl₃) δ: 1.14 (d, J=7.4 Hz, 3H), 1.24-1.34 (m, 1H), 1.80 (d,J=14.8 Hz, 1H), 1.88-2.04 (m, 2H), 2.60-2.70 (m, 1H), 2.70-2.82 (m, 1H),3.09 (t, J=11.8 Hz, 1H), 3.59 (d, J=13.5 Hz, 1H), 4.37 (d, J=11.5 Hz,1H), 4.45 (d, J=13.2 Hz, 1H), 4.81 (d, J=13.2 Hz, 1H), 5.44-5.54 (m,1H), 5.58 (d, J=13.5 Hz, 1H), 5.83 (d, J=7.7 Hz, 1H), 6.00 (s, 1H), 6.73(d, J=7.7 Hz, 1H), 6.78-6.85 (m, 1H), 6.95 (d, J=7.7 Hz, 1H), 7.07-7.21(m, 4H).

Reference Example 755

¹H-NMR (CDCl₃) δ: 1.08 (d, J=7.4 Hz, 3H), 2.50 (s, 6H), 3.53 (d, J=14.0Hz, 1H), 4.26 (d, J=13.2 Hz, 1H), 4.74 (d, J=13.2 Hz, 1H), 5.35-5.45 (m,1H), 5.87 (d, J=14.0 Hz, 1H), 6.05 (s, 1H), 6.75 (d, J=7.7 Hz, 1H), 6.84(t, J=6.5 Hz, 1H), 7.07-7.18 (m, 4H), 7.33-7.40 (m, 2H).

Reference Example 756

¹H-NMR (CDCl₃) δ: 1.22 (d, J=6.7 Hz, 3H), 3.49-3.60 (m, 1H), 4.50-4.61(m, 1H), 4.71 (d, J=14.8 Hz, 1H), 4.90 (d, J=11.6 Hz, 1H), 5.40-5.65 (m,2H), 5.75-5.82 (m, 2H), 6.03-6.16 (m, 1H), 6.37 (d, J=9.8 Hz, 1H), 6.69(d, J=7.3 Hz, 1H), 6.78-6.87 (m, 2H), 6.97 (d, J=7.3 Hz, 1H), 7.07-7.14(m, 2H).

Reference Example 757

¹H-NMR (CDCl₃) δ: 0.70 (d, J=7.1 Hz, 3H), 2.46 (s, 3H), 3.73 (d, J=13.5Hz, 1H), 4.51 (d, J=13.2 Hz, 1H), 4.87 (d, J=13.2 Hz, 1H), 5.41-5.52 (m,1H), 5.70 (d, J=13.5 Hz, 1H), 5.85 (d, J=7.7 Hz, 1H), 5.92 (s, 1H), 6.38(s, 1H), 6.79-6.90 (m, 2H), 7.07-7.11 (m, 2H), 7.17 (d, J=8.0 Hz, 1H),7.22 (d, J=7.7 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H).

Reference Example 758

¹H-NMR (CDCl₃) δ: 1.09 (d, J=7.1 Hz, 3H), 2.50 (s, 6H), 2.52 (s, 3H),3.51 (d, J=13.7 Hz, 1H), 4.27 (d, J=13.2 Hz, 1H), 4.73 (d, J=13.2 Hz,1H), 5.35-5.48 (m, 1H), 5.93 (d, J=13.7 Hz, 1H), 6.04 (s, 1H), 6.70-6.83(m, 2H), 7.00-7.16 (m, 4H), 7.36 (t, J=7.7 Hz, 1H), 7.84 (s, 1H).

Reference Example 759

First Step

Compound 759A (124 mg, 0.35 mmol) was suspended in dichloromethane.4,9-dihydrobenzo[e]thieno[2,3-b]thiepin-ol (82 mg, 0.35 mmol) anddichloroacetic acid (87 μL, 1.05 mmol) were added, and the mixture wasstirred at room temperature for 1 hour. Water was added, and the mixturewas extracted with chloroform. The organic layer was washed with waterand aqueous saturated sodium chloride solution, and then dried withanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was purified by silica gelchromatography (chloroform-methanol) to obtain compound 759B (180 mg,yield 90%).

MS: m/z=572.29 [M+H]⁺.

Second Step

Compound 759B (108 mg, 0.18 mmol) was suspended in DMA. Paraformaldehyde(113 mg, 0.38 mmol) and BEMP (0.33 mL, 1.13 mmol), and the mixture wasstirred for 5 minutes under ice-cooling, and then stirred at roomtemperature for 2 days. Thereafter, tosyl chloride (72 mg, 0.38 mmol)was added, and the mixture was stirred for 3 days. A saturated ammoniachloride water was added, and the precipitated solid was filtered. Theresulting residue was purified by silica gel column chromatography(chloroform-methanol) to obtain compound 759C (16 mg, yield 15%).

MS: m/z=584.25 [M+H]⁺

Third Step

Compound 759C (16 mg, 0.03 mmol) was suspended in DMF. Lithium chloride(17 mg, 0.41 mmol) was added, and the mixture was stirred at 90° C. for7 hours. A 1M aqueous hydrochloric acid solution was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and aqueous saturated sodium chloride solution, and thendried with anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by diolsilica gel chromatography (chloroform-methanol) to obtain compound 759(9 mg, 0.02 mmol).

MS: m/z=494.18 [M+H]⁺

Reference Example 760

MS: m/z=505.11 [M+H]⁺

Reference Example 761

MS: m/z=507.09 [M+H]⁺

Reference Example 762

MS: m/z=556.18 [M+H]⁺

Reference Example 763

MS: m/z=540.12 [M+H]⁺

Reference Example 764

MS: m/z=522.05 [M+H]⁺

Reference Example 765

First Step

Compound 765A (722 mg, 2.43 mmol) was suspended in DMF. N-Bocazetidinone (1.25 g, 7.30 mmol) and cesium carbonate (2.96 g, 12.16mmol) were added, and the mixture was stirred for 30 minutes underice-cooling, and then stirred at room temperature for 30 minutes.Thereafter, 5-chlorodibenzosuberane (1.67 g, 7.30 mmol) was added, andthe mixture was stirred for 3 hours. Insolubles were separated byfiltration, then a 0.5M aqueous hydrochloric acid solution was added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and aqueous saturated sodium chloride solution, andthen dried with anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and the resulting residue was purified bysilica gel chromatography (chloroform-methanol) to obtain compound 765B(176 mg, yield 11%).

MS: m/z=663.33 [M+H]⁺.

Second Step

Compound 765B (176 mg, 0.27 mmol) was suspended in DMA. Lithium chloride(113 mg, 2.66 mmol) was added, and the mixture was stirred at 100° C.for 2 hours. A 0.5M aqueous hydrochloric acid solution was added, andthe precipitated solid was filtered to obtain compound 765C (92 mg, 0.16mmol).

MS: m/z=573.29 [M+H]⁺

Third Step

To compound 765C (45 mg, 0.08 mmol) was added 4N HC/dioxane (0.68 mL,2.75 mmol), and the mixture was stirred for 3 hours under ice-cooling.The reaction solution was diluted with diisopropyl ether, and thegenerated solid was filtered to obtain compound 765D (29 mg, 0.057mmol).

MS: m/z=474.19 [M+H]⁺

Fourth Step

Compound 765D (31 mg, 0.06 mmol) was suspended in dichloromethane. 37%formaldehyde (25 μL, 0.91 mmol), triethylamine (10 μL, 0.07 mmol),acetic acid (5 μL, 0.09 mmol), and NaBH(OAc)₃ (25 mg, 0.12 mmol) wereadded, and the mixture was stirred at room temperature for 1 hour.Saturated sodium bicarbonate water was added, the mixture was extractedwith chloroform. The organic layer was washed with water and aqueoussaturated sodium chloride solution, and then dried with anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,then the residue was solidified with hexane to obtain compound 765 (15mg, 0.03 mmol).

MS: m/z=487.25 [M+H]⁺

Reference Example 766

MS: m/z=461.23 [M+H]⁺

Reference Example 767

First Step

Compound 767A (87 mg, 0.37 mmol) was suspended in dichloromethane.Thionyl chloride (54 μL, 0.75 mmol) was added, and the mixture washeated to reflux for 2 hours. After concentration of the reactionsolution, the resulting residue was solidified with hexane to obtaincompound 767B (48 mg, yield 51%).

Second Step

Compound 767B (70 mg, 0.19 mmol) was suspended in DMF. Compound 12 (48mg, 0.19 mmol) and cesium carbonate (186 mg, 0.57 mmol) were added, andthe mixture was stirred at room temperature for 2 hours. Insolubles wereseparated by filtration, then water was added to the filtrate, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and aqueous saturated sodium chloride solution, and thendried with anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the resulting residue was purified by silicagel chromatography (chloroform-methanol) to obtain compound 767C (32 mg,0.06 mmol).

MS: m/z=583.16 [M+H]⁺

Third Step

Compound 767C (31 mg, 0.05 mmol) was suspended in THF-methanol. 10%palladium carbon (15 mg) was added, and the mixture was stirred at roomtemperature for 24 hours under hydrogen atmosphere. Insolubles wereseparated by filtration, then the filtrate was concentrated, and theresulting residue was purified by diol silica gel chromatography(chloroform-methanol) to obtain compound 767 (6 mg, 0.01 mmol).

MS: m/z=493.16 [M+H]⁺

Reference Example 768

MS: m/z=536.19 [M+H]⁺

Reference Example 769

MS: m/z=531.49 [M+H]⁺

Reference Example 770

MS: m/z=584.09 [M+H]⁺

Reference Example 771

MS: m/z=586.07 [M+H]⁺

Reference Example 772

MS: m/z=540.14 [M+H]⁺

Reference Example 773

MS: m/z=540.14 [M+H]⁺

Reference Examples 774 and 775

First Step

Compound 774A (111 mg, 0.20 mmol) was suspended in DMA. Paraformaldehyde(11 mg, 0.39 mmol) and BEMP (0.34 mL, 1.17 mmol), and the mixture wasstirred at room temperature for 1.5 hours. Thereafter, tosyl chloride(74 mg, 0.39 mmol) was added, and the mixture was stirred for 2 hours. Asaturated chloride ammonia water was added, and the precipitated solidwas filtered. The resulting solid was purified by silica gelchromatography (hexane-ethyl acetate) to obtain compound 774B (16 mg,yield 14%).

MS: m/z=595.18 [M+H]⁺

Second Step

Compound 774B (16 mg, 0.03 mmol) was suspended in DMA. Lithium chloride(11 mg, 0.27 mmol) was added, and the mixture was stirred at 100° C. for3 hours. A 0.5M aqueous hydrochloric acid solution was added, and thegenerated solid was filtered to obtain compound 774 (3 mg, 0.006 mmol).

MS: m/z=505.11 [M+H]⁺

Third Step

Compound 774B (21 mg, 0.04 mmol) was suspended in methanol. 10%palladium carbon (15 mg) was added, and the mixture was stirred at roomtemperature for 20 hours under hydrogen atmosphere. Insolubles wereseparated by filtration, then the filtrate was concentrated, and theresulting residue was suspended in DMA. Lithium chloride (12 mg, 0.28mmol) was added, and the mixture was stirred at 100° C. for 3 hours. A0.5M aqueous hydrochloric acid solution was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand aqueous saturated sodium chloride solution, and then dried withanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, and the resulting residue was solidified with diisopropylether to obtain compound 775 (9 mg, 0.02 mmol).

MS: m/z=507.13 [M+H]⁺

The following EX-1 to EX-29 can be also synthesized like the Referenceexamples, and are a preferable embodiment of the parent compound.

Hereinbelow, compounds of Examples 1 to 241 in connection with thepresent invention are shown.

Example 1

First Step

To a dichloromethane (1 ml) solution of compound 1-a (50 mg, 0.0900mmol) and triethylamine (46 mg, 0.45 mmol) were added acetic acidanhydride (28 mg, 0.27 mmol) and DMAP (11 mg, 0.0090 mmol) at roomtemperature, and the mixture was stirred for 3 hours while the sametemperature was retained. The reaction solution was diluted withdichloromethane (10 ml), and then water was added. The dichloromethanelayer was separated, and the aqueous layer was extracted withdichloromethane once. After the combined extracts were dried with sodiumsulfate, the solvent was distilled off, and the resulting solid waswashed with ethyl acetate-diisopropyl ether to obtain 27 mg of compoundof Example 1.

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.5 Hz), 2.44 (3H, s), 3.98 (1H, d,J=14.7 Hz), 4.41 (1H, d, J=13.5 Hz), 4.95 (1H, d, J=13.2 Hz), 5.25 (1H,s), 5.46-5.57 (1H, m), 5.86 (1H, d, J=14.7 Hz), 5.97 (1H, d, J=7.8 Hz),6.89-6.94 (2H, m), 7.06-7.21 (3H, m), 7.39 (2H, d, J=3.9 Hz), 7.78-7.82(1H, m).

Example 2

¹H-NMR (CDCl₃) δ: 1.02 (3H, d, J=6.6 Hz), 1.06 (3H, d, J=6.9 Hz),3.58-3.62 (1H, m), 4.36 (1H, d, J=13.2 Hz), 4.70 (1H, brs), 4.82-4.91(1H, m), 5.19 (1H, d, J=8.4 Hz), 5.67-5.75 (1H, m), 6.02 (1H, brs), 6.86(1H, brs), 7.00-7.08 (3H, m), 7.13-7.51 (4H, m), 7.55-7.63 (2H, m), 8.07(1H, d, J=7.5 Hz), 8.26 (2H, d, J=7.5 Hz).

Example 3

¹H-NMR (CDCl₃) δ: 1.03 (3H, d, J=6.6 Hz), 1.08 (3H, d, J=8.4 Hz), 1.45(9H, s), 3.56-3.60 (1H, m), 4.33 (1H, d, J=13.2 Hz), 4.79 (2H, brs),5.15 (1H, brs), 5.68 (1H, brs), 5.90 (1H, brs), 6.84 (1H, brs), 6.94(1H, brs), 7.05-7.06 (2H, m), 7.15-7.27 (3H, m), 7.33-7.43 (2H, m).

Example 4

MS: m/z=566 [M+H]⁺,

Rf: 0.56 (CHCl3:MeOH=9:1).

Example 5

MS: m/z=566 [M+H]⁺,

Rf: 0.52 (CHCl3:MeOH=9:1).

Example 6

MS: m/z=582 [M+H]⁺,

Rf: 0.56 (CHCl3:MeOH=9:1).

Example 7

MS: m/z=582 [M+H]⁺,

Rf: 0.52 (CHCl3:MeOH=9:1).

Example 8

MS: m/z=582 [M+H]⁺,

Rf: 0.56 (CHCl3:MeOH=9:1).

Example 9

MS: m/z=582 [M+H]⁺,

Rf: 0.52 (CHCl3:MeOH=9:1).

Example 10

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, J=7.3 Hz), 2.43 (3H, s), 3.64 (1H, d,J=13.6 Hz), 4.42 (1H, d, J=12.9 Hz), 4.91 (1H, d, J=12.9 Hz), 5.18 (1H,s), 5.49 (1H, m), 5.74 (1H, d, J=13.6 Hz), 6.00 (1H, d, J=7.7 Hz), 6.79(1H, t, J=7.7 Hz), 6.87 (1H, m), 6.97 (1H, dt, J=2.6, 8.0 Hz), 7.08-7.18(3H, m), 7.45 (1H, dd, J=1.5, 8.0 Hz).

MS: m/z=627 [M+H]⁺.

Rf: 0.53 (CHCl₃:MeOH=9:1).

Example 11

MS: m/z=627 [M+H]⁺

Rf: 0.46 (CHCl₃:MeOH=9:1).

Example 12

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=7.2 Hz), 2.32 (2H, m), 2.43 (3H, s),2.65 (2H, t, J=8.1 Hz), 3.64 (1H, d, J=14.2 Hz), 3.86 (2H, m), 4.56 (1H,d, J=13.5 Hz), 4.91 (1H, d, J=13.5 Hz), 5.17 (1H, s), 5.44 (1H, m), 5.50(1H, d, J=14.2 Hz), 5.96 (1H, d, J=7.8 Hz), 6.88 (1H, m), 7.03-7.16 (3H,m), 7.20 (1H, d, J=7.8 Hz), 7.30 (3H, m).

MS: m/z=613 [M+H]⁺.

Rf: 0.5 (CHCl₃:MeOH=9:1).

Example 13

MS: m/z=613 [M+H]⁺,

Rf: 0.4 (CHCl₃:MeOH=9:1).

Example 14

MS: m/z=582 [M+H]⁺,

Rf: 0.56 (CHCl₃:MeOH=9:1).

Example 15

MS: m/z=582 [M+H]⁺,

Rf: 0.46 (CHCl₃:MeOH=9:1).

Example 16

MS: m/z=562 [M+H]⁺,

Rf: 0.53 (CHCl₃:MeOH=9:1).

Example 17

MS: m/z=562 [M+H]⁺,

Rf: 0.46 (CHCl₃:MeOH=9:1).

Example 18

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, J=6.1 Hz), 2.42 (3H, s), 4.31 (1H, d,J=13.9 Hz), 4.57 (1H, d, J=12.6 Hz), 4.97 (1H, d, J=12.6 Hz), 5.26 (1H,s), 5.28 (1H, m), 5.62 (1H, d, J=13.9 Hz), 5.96 (1H, d, J=7.8 Hz), 6.87(1H, m), 7.04-7.12 (3H, m), 7.19 (1H, t, J=7.9 Hz), 7.32 (1H, d, J=7.5Hz), 7.49 (1H, dd, J=1.2, 7.9 Hz).

MS: m/z=564 [M+H]⁺.

Example 19

¹H-NMR (DMSO-d₆) δ: 0.97-1.09 (9H, m), 1.68 (2H, m), 2.55 (2H, t, J=7.2Hz), 3.88 (1H, d, J=13.3 Hz), 4.27 (1H, d, J=13.7 Hz), 4.59 (1H, m),4.99 (1H, d, J=13.6 Hz), 5.33 (1H, s), 5.73 (2H, dd, J=53.9, 10.8 Hz),6.83-7.48 (9H, m).

MS: m/z=504 [M+H]⁺.

Example 20

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=7.3 Hz), 2.44 (3H, s), 3.61 (1H, d,J=13.4 Hz), 4.46 (1H, d, J=13.1 Hz), 4.91 (1H, d, J=13.3 Hz), 5.12 (1H,s), 5.42-5.57 (1H, m), 5.64 (1H, d, J=13.4 Hz), 5.98 (1H, d, J=7.8 Hz),6.87 (2H, s), 6.99-7.61 (7H, m).

MS: m/z=530 [M+H]⁺.

Example 21

Example 22

Example 23

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=7.3 Hz), 2.44 (3H, s), 3.61 (1H, d,J=13.4 Hz), 4.46 (1H, d, J=13.1 Hz), 4.91 (1H, d, J=13.3 Hz), 5.12 (1H,s), 5.42-5.57 (1H, m), 5.64 (1H, d, J=13.4 Hz), 5.98 (1H, d, J=7.8 Hz),6.87 (2H, s), 6.99-7.61 (7H, m).

Example 24

¹H-NMR (CDCl₃) δ: 1.34 (3H, d, J=7.3 Hz), 2.43 (3H, s), 3.60 (1H, d,J=13.3 Hz), 4.57 (1H, d, J=12.5 Hz), 4.97 (1H, d, J=12.5 Hz), 5.23 (1H,s), 5.29 (1H, m), 5.66 (1H, d, J=13.1 Hz), 5.97 (1H, d, J=7.9 Hz), 6.87(2H, s), 7.05-7.42 (8H, m).

Example 25

Example 26

Example 27

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, J=7.4 Hz), 2.46 (3H, s), 3.63 (1H, d,J=13.5 Hz), 4.46 (1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 5.14 (1H,s), 5.51 (1H, m), 5.68 (1H, d, J=13.5 Hz), 6.07 (1H, d, J=8.0 Hz), 6.63(1H, t, J=8.0 Hz), 6.84 (2H, m), 7.18-7.49 (6H, m).

MS: m/z=541 [M+H]⁺.

Example 28

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.2 Hz), 2.41 (3H, d, J=15.1 Hz), 3.62(1H, d, J=13.6 Hz), 4.44 (1H, d, J=13.3 Hz), 4.93 (1H, d, J=13.1 Hz),5.06 (1H, s), 5.50 (1H, m), 5.58 (1H, d, J=13.4 Hz), 5.98 (1H, d, J=7.8Hz), 6.88-7.39 (8H, m).

Example 29

¹H-NMR (CDCl₃) δ: 1.35 (3H, d, J=7.5 Hz), 2.42 (3H, s), 3.61 (1H, d,J=13.4 Hz), 4.56 (1H, d, J=12.8 Hz), 4.99 (1H, d, J=12.8 Hz), 5.16 (1H,s), 5.23-5.38 (1H, m), 5.59 (1H, d, J=13.6 Hz), 5.97 (1H, d, J=7.8 Hz),6.91-7.38 (8H, m).

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 36

Example 37

Example 38

Example 39

¹H-NMR (CDCl₃) δ: 1.35 (3H, d, J=7.5 Hz), 2.42 (3H, s), 3.61 (1H, d,J=13.4 Hz), 4.56 (1H, d, J=12.8 Hz), 4.99 (1H, d, J=12.8 Hz), 5.16 (1H,s), 5.23-5.38 (1H, m), 5.59 (1H, d, J=13.6 Hz), 5.97 (1H, d, J=7.8 Hz),6.91-7.38 (8H, m).

Example 40

Example 41

Example 42

Example 43

Example 44

Example 45

Example 46

Example 47

Example 48

Example 49

Example 50

MS: m/z=548 [M+H]⁺.

Example 51

Example 52

Example 53

Example 54

Example 55

Example 56

Example 57

Example 58

Example 59

Example 60

Example 61

Example 62

Example 63

Example 64

¹H-NMR (DMSO-d₆) δ: 1.07 (4H, m), 1.17 (3H, d, J=6.9 Hz), 1.88 (1H, m),3.88 (1H, d, J=13.6 Hz), 4.38 (1H, d, J=13.6 Hz), 5.11 (1H, d, J=13.4Hz), 5.46 (1H, m), 5.51 (1H, s), 5.63 (1H, d, J=13.3 Hz), 5.87 (1H, d,J=7.8 Hz), 6.84-7.60 (9H, m).

MS: m/z=556 [M+H]⁺.

Example 65

Example 66

Example 67

MS: m/z=614 [M+H]⁺.

Example 68

Example 69

Example 70

Example 71

Example 72

Example 73

Example 74

Example 75

Example 76

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=7.2 Hz), 2.44 (3H, s), 4.22 (1H, d,J=13.7 Hz), 4.44 (1H, d, J=13.3 Hz), 4.93 (1H, d, J=13.6 Hz), 5.23 (1H,s), 5.42 (1H, d, J=15.7 Hz), 5.50 (1H, m), 6.00 (1H, d, J=7.9 Hz),6.85-7.29 (7H, m).

MS: m/z=582 [M+H]⁺.

Example 77

Example 78

Example 79

Example 80

Example 81

Example 82

Example 83

MS: m/z=609.90 [M+H]⁺.

Example 84

MS: m/z=609.90 [M+H]⁺.

Example 85

MS: m/z=555.20 [M+H]⁺.

Example 86

MS: m/z=555.20 [M+H]⁺.

Example 87

¹H-NMR (CDCl₃) δ: 1.34 (3H, d, J=7.4 Hz), 2.42 (3H, s), 3.60 (1H, d,J=13.3 Hz), 4.56 (1H, d, J=12.7 Hz), 4.96 (1H, d, J=12.4 Hz), 5.20-5.34(2H, m), 5.65 (1H, d, J=13.5 Hz), 5.97 (1H, d, J=7.9 Hz), 6.76-7.41 (9H,m).

MS: m/z=530 [M+H]⁺.

Example 88

¹H-NMR (CDCl₃) δ: 1.34 (3H, d, J=7.5 Hz), 1.39 (6H, d, J=6.8 Hz),2.92-3.00 (1H, m), 3.59 (1H, d, J=13.1 Hz), 4.56 (1H, d, J=12.7 Hz),4.97 (1H, d, J=12.2 Hz), 5.22-5.30 (2H, m), 5.65 (1H, d, J=13.7 Hz),6.00 (1H, d, 7.9 Hz), 6.90-7.39 (9H, m).

MS: m/z=558 [M+H]⁺.

Example 89

¹H-NMR (CDCl₃) δ: 1.26-1.35 (6H, m), 2.76 (2H, q, J=7.3 Hz), 3.59 (1H,d, J=13.2 Hz), 4.56 (1H, d, J=12.6 Hz), 4.96 (1H, d, J=12.8 Hz),5.22-5.30 (2H, m), 5.66 (1H, d, J=13.4 Hz), 5.95 (1H, d, J=7.7 Hz),6.89-7.42 (9H, m).

MS: m/z=544 [M+H]⁺.

Example 90

¹H-NMR (CDCl₃) δ: 1.12 (3H, d, J=7.2 Hz), 1.40 (6H, d, J=6.9 Hz),2.93-3.02 (1H, m), 3.60 (1H, d, J=13.1 Hz), 4.44 (1H, d, J=13.1 Hz),4.90 (1H, d, J=12.9 Hz), 5.12 (1H, s), 5.46-5.66 (2H, m), 5.93 (1H, d,J=7.7 Hz), 6.89 (2H, brs), 7.06-7.28 (5H, m), 7.35-7.44 (2H, m).

MS: m/z=558 [M+H]⁺.

Example 91

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, J=6.1 Hz), 1.31 (3H, t, J=7.5 Hz), 2.77(2H, q, J=7.6 Hz), 3.60 (1H, d, J=13.4 Hz), 4.45 (1H, d, J=13.2 Hz),4.90 (1H, d, J=13.3 Hz), 5.12 (1H, s), 5.44-5.66 (2H, m), 5.95 (1H, d,J=7.9 Hz), 6.89 (2H, brs), 7.06-7.45 (7H, m).

MS: m/z=544 [M+H]⁺.

Example 92

¹H-NMR (CDCl₃) δ: 1.09-1.14 (9H, m), 2.26-2.35 (1H, m), 2.60 (2H, d,J=6.6 Hz), 3.60 (1H, d, J=13.5 Hz), 4.44 (1H, d, J=13.0 Hz), 4.90 (1H,d, J=12.7 Hz), 5.11 (1H, s), 5.46-5.65 (2H, m), 5.94 (1H, d, J=8.1 Hz),6.88 (2H, brs), 7.07-7.44 (7H, m).

MS: m/z=572 [M+H]⁺.

Example 93

¹H-NMR (CDCl₃) δ: 1.05-1.14 (6H, m), 1.81-1.88 (2H, m), 2.71 (2H, t,J=7.4 Hz), 3.61 (1H, d, J=13.4 Hz), 4.45 (1H, d, J=13.4 Hz), 4.91 (1H,d, J=13.3 Hz), 5.12 (1H, s), 5.47-5.66 (2H, m), 5.95 (1H, d, J=8.0 Hz),6.89 (2H, brs), 7.07-7.45 (7H, m).

MS: m/z=558 [M+H]⁺.

Example 94

MS: m/z=572 [M+H]⁺.

Example 95

¹H-NMR (DMSO-d₆) δ: 1.03 (3H, d, J=8.0 Hz), 2.29 (3H, s), 3.98 (1H, d,J=12.0 Hz), 4.53 (1H, d, 12.0 Hz), 5.13 (1H, d, 12.0 Hz), 5.47 (1H, m),5.66 (1H, d, J=12.0 Hz), 5.79 (1H, s), 5.92 (1H, d, J=8.0 Hz), 6.81 (1H,d, 8.0 Hz), 6.91 (1H, m), 7.13-7.22 (2H, m), 7.27 (1H, d, J=8.0 Hz),7.45 (2H, m), 7.51 (1H, m).

MS: m/z=564 [M+H]⁺. RT=2.10 min.

Example 96

¹H-NMR (DMSO-d₆) δ: 1.40 (3H, d, J=8.0 Hz), 2.42 (3H, s), 3.62 (1H, d,J=12.0 Hz), 4.48 (1H, d, 12.0 Hz), 5.02 (2H, m), 5.64 (1H, m), 5.97 (1H,d, J=8.0 Hz), 6.05 (1H, s), 6.91 (1H, m), 7.05-7.15 (2H, m), 7.20-7.35(5H, m)

MS: m/z=564 [M+H]⁺. RT=2.11 min.

Example 97

¹H-NMR (DMSO-d₆) δ: 0.94-1.02 (6H, m), 3.89 (1H, d, J=13.42 Hz), 4.29(1H, d, J=13.57 Hz), 4.54 (1H, t, J=6.79 Hz), 5.04 (1H, d, J=13.42 Hz),5.50 (2H, t, J=51.02 Hz), 5.91 (1H, d, J=7.78 Hz), 6.87-7.26 (5H, m),7.42 (4H, dt, J=21.66, 7.66 Hz), 7.64-7.68 (1H, m), 8.40-8.43 (1H, m),8.90 (1H, dd, J=4.73, 1.68 Hz), 9.20 (1H, d, J=1.68 Hz).

MS: m/z=539.00 [M+H]⁺.

Example 98

To a DMF (1 ml) solution of Tetrahydro-2H-pyran-4-carboxylic acid (125mg, 0.958 mmol) and triethylamine (194 mg, 1.92 mmol) was added dropwiseethyl chloroformate (94 mg, 0.862 mmol) at room temperature. After thereaction solution was stirred at the same temperature for 5 minutes,compound 98-a (50 mg, 0.0958 mmol) was added, and the mixture wasstirred for 5 hours. The reaction solution was diluted by ethyl acetate(10 ml), and water was added. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate once. The extract waswashed with water three times, and dried with sodium sulfate, and thesolvent was distilled off. the resulting solid was washed with ethylacetate-diisopropyl ether to obtain 30 mg of compound of Example 98.

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.5 Hz), 1.98-2.13 (4H, m), 2.95-3.03(1H, m), 3.40-3.57 (2H, m), 3.95-4.14 (2H, m), 4.31 (1H, d, J=14.1 Hz),4.45 (1H, d, J=13.2 Hz), 4.92 (1H, d, J=13.5 Hz), 5.16 (1H, s),5.45-5.57 (1H, m), 5.60 (1H, d, J=14.1 Hz), 5.95 (1H, d, J=7.8 Hz), 6.91(2H, brs), 7.09-7.26 (5H, m), 7.53 (1H, d, J=8.1 hz).

Example 99

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, J=7.2 Hz), 1.98-2.14 (4H, m), 2.95-3.05(1H, m), 3.49-3.57 (3H, m), 4.03-4.09 (2H, m), 4.44 (1H, d, J=13.2 Hz),4.91 (1H, d, J=12.9 Hz), 5.13 (1H, s), 5.44-5.54 (1H, m), 5.66 (1H, d,J=13.5 Hz), 5.94 (1H, d, J=8.1 Hz), 6.91-6.99 (3H, m), 7.07-7.22 (5H,m).

Example 100

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, J=7.2 Hz), 2.01-2.13 (4H, m), 2.95-3.04(1H, m), 3.49-3.57 (2H, m), 3.96-4.08 (3H, m), 4.41 (1H, d, J=13.5 Hz),4.94 (1H, d, J=13.5 Hz), 5.26 (1H, s), 5.45-5.55 (1H, m), 5.86 (1H, d,J=14.7 Hz), 5.95 (1H, d, J=7.5 Hz), 6.91-6.93 (2H, m), 7.07-7.19 (3H,m), 7.38-7.39 (2H, m), 7.79-7.82 (1H, m).

Example 101

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=7.2 Hz), 1.98-2.12 (4H, m), 2.94-3.04(1H, m), 3.48-3.56 (2H, m), 4.04-4.07 (2H, m), 4.21 (1H, d, J=13.8 Hz),4.45 (1H, d, J=13.2 Hz), 4.92 (1H, d, J=13.2 Hz), 5.20 (1H, s), 5.37(1H, d, J=13.5 Hz), 5.43-5.54 (1H, m), 5.93 (1H, d, J=7.8 Hz), 6.77 (1H,brs), 6.82-6.86 (1H, m), 6.97-6.99 (1H, m), 7.04 (2H, d, J=7.5 Hz),7.17-7.25 (3H, m).

Example 102

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=7.2 Hz), 2.50 (6H, s), 3.55-3.68 (2H,m), 4.31 (1H, d, J=13.8 Hz), 4.44 (1H, d, J=13.2 Hz), 4.92 (1H, d,J=13.2 Hz), 5.45-5.58 (1H, m), 5.61 (1H, d, J=13.8 Hz), 5.95 (1H, d,J=7.8 Hz), 6.90 (2H, brs), 7.07-7.11 (3H, m), 7.16-7.25 (2H, m), 7.52(2H, d, J=6.9 Hz).

Example 103

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.2 Hz), 2.17 (2H, s), 3.32 (3H, s),3.63-3.66 (2H, m), 3.87-3.90 (2H, m), 4.31 (1H, d, J=13.8 Hz), 4.45 (1H,d, J=13.5 Hz), 6.60 (2H, d, J=2.1 Hz), 4.92 (1H, d, J=12.6 Hz), 5.15(1H, s), 5.44-5.54 (1H, m), 5.60 (1H, d, J=13.8 Hz), 5.95 (1H, d, J=7.8Hz), 6.89-6.90 (2H, m), 7.07-7.14 (3H, m), 7.16-7.25 (2H, m), 7.52 (1H,d, J=6.9 Hz).

Example 104

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=7.2 Hz), 2.09 (4H, m), 3.03 (1H, dm),3.55 (2H, m), 4.10 (2H, m), 4.26 (1H, d, J=13.6 Hz), 4.48 (1H, d, J=13.1Hz), 4.96 (1H, d, J=12.8 Hz), 5.28 (1H, s), 5.46 (1H, d, J=13.4 Hz),5.54 (1H, d, J=8.1 Hz), 6.03 (1H, d, J=7.9 Hz), 6.94-7.34 (7H, m).

MS: m/z=652[M+H]⁺.

Example 105

According to the method shown in Bioorganic & Medicinal ChemistryLetters; English; 14; 12; 2004; 3231-3234, ethyl chloroformate (93 mg,0.862 mmol) was added to a DMF (1 ml) solution of2-(tert-butyldimethylsilyloxy)acetic acid (82 mg, 0.958 mmol) andtriethylamine (194 mg, 1.92 mmol) at room temperature, and the mixturewas stirred at the same temperature for 3 minutes. Compound 98-a (50 mg,0.0958 mmol) was added to the reaction solution, and the mixture wasfurther stirred for 1 hour. The reaction solution was diluted with ethylacetate (10 ml), and water was added. The organic layer was separated,and the aqueous layer was extracted with ethyl acetate once. The extractwas washed with water three times, and dried with sodium sulfate, andthe solvent was distilled off. The resulting crude product was dissolvedin THF (2 ml), a 1M THF solution (0.287 ml, 0.287 mmol) of TBAF wasadded at room temperature, and the mixture was stirred at the sametemperature for 30 minutes. Water was added to the reaction solution,followed by extraction with ethyl acetate two times. The extract wasdried with sodium sulfate, and the solvent was distilled off, then theresulting solid was washed with ethyl acetate-diisopropyl ether toobtain 30 mg of compound of Example 105.

¹H-NMR (CDCl₃) δ: 1.24 (3H, d, J=7.2 Hz), 4.36 (1H, d, J=14.1 Hz), 4.52(1H, d, J=13.2 Hz), 4.62 (1H, d, J=16.5 Hz), 4.90-4.97 (2H, m), 5.14(1H, s), 5.51-5.62 (2H, m), 6.12 (1H, d, J=7.8 Hz), 6.68 (1H, d, J=7.2Hz), 6.84-6.90 (1H, m), 7.10-7.18 (3H, m), 7.20-7.24 (1H, m), 7.37 (1H,d, J=7.8 Hz), 7.55 (1H, d, J=6.9 Hz).

Example 106

(S)-2-(tert-butoxycarbonylamino)propanoic acid (301 mg, 1.59 mmol) wasdissolved in THF (2 ml), N-methylmorpholine (0.175 ml, 1.59 mmol) andisobutyl chloroformate (0.209 ml, 1.59 mmol) were added at 0° C., andthe mixture was stirred for 15 minutes. A dichloromethane solution (1ml) of 106-a (69.0 mg, 0.159 mmol) synthesized according to Example wasadded at 0° C., and the mixture was stirred at room temperature for 4hours. To the reaction solution was added water, the mixture wasextracted with ethyl acetate, and the organic layer was dried withsodium sulfate. The solvent was distilled off under reduced pressure,and the resulting crude product was purified by silica gel columnchromatography, and eluted with chloroform-methanol (97:3, v/v). Theresulting product was solidified by adding dichloromethane-diisopropylether-diethyl ether to obtain 40 mg of compound of Example 106 as awhite solid.

Example 107

First Step

To a methanol (80 mL) solution of (R)-methyl2,2-dimethyl-1,3-dioxolane-4-carboxylate (107-a, 11.22 g, 70.1 mmol) wasadded sodium hydroxide monohydrate (2.94 g, 70.1 mmol) at roomtemperature, and the mixture was stirred for 3 hours. The solvent wasdistilled off under reduced pressure, to the resulting residue was added2N hydrochloric acid (35 mL) under ice-cooling, and the mixture wasextracted with chloromethane (100 mL×2). The organic layer was washedwith water (50 mL), and dried with magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude product ofcompound 107-b was used in a next reaction without purification.

Second Step

To a dichloromethane (2 mL) solution of compound 98-a (41.7 mg, 0.285mmol), triethylamine (0.106 mL, 0.765 mmol) and 4-dimethylaminopyridine(5.7 mg, 0.047 mmol) was added 2-methyl-6-nitrobenzoic anhydride (100mg, 0.290 mmol) at room temperature, and the mixture was stirred for 10minutes. Compound 5C (51.7 mg, 0.099 mmol) was added to the reactionsolution, and the mixture was stirred for 1.5 hours. To the reactionsolution was added water (2 mL), then the mixture was extracted withdichloromethane, and the organic layer was dried with sodium sulfate.The solvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel column chromatography (ethylacetate/n-hexane=60% 100%) to obtain compound of Example 107 (40.4 mg,63%) as a white solid.

MS: m/z=650.35 [M+H]⁺.

Example 108

First Step

To a dichloromethane (1 mL) solution of compound 98-a (50.0 mg, 0.096mmol), triethylamine (0.0660 mL, 0.476 mmol) and N-methylimidazole(0.0038 mL, 0.048 mmol) was added 3-methoxypropionyl chloride (33.0 mg,0.269 mmol) at room temperature, and the mixture was stirred for 16hours. To the reaction solution were added water (1 mL) and hydrochloricacid (2M, 1 mL), the mixture was extracted with dichloromethane, and theorganic layer was dried with sodium sulfate. The solvent was distilledoff under reduced pressure, the resulting residue was purified by silicagel column chromatography (ethyl acetate/n-hexane=60%→100%), and theresulting product was converted into a powder with ethylacetate-isopropyl ether to obtain compound of Example 108 (47.0 mg, 81%)as a white solid.

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.2 Hz), 3.03 (2H, t, J=6.9 Hz), 3.43(3H, s), 3.85 (2H, m), 4.31 (1H, d, J=13.7 Hz), 4.45 (1H, d, J=13.2 Hz),4.92 (1H, d, J=13.2 Hz), 5.16 (1H, s), 5.52 (1H, m), 5.60 (1H, d, J=13.7Hz), 5.96 (1H, d, J=8.1 Hz), 6.90 (2H, m), 7.10-7.23 (5H, m), 7.53 (1H,d, J=8.1 Hz).

MS: m/z=608.20 [M]⁺.

Example 109

According to Example 108, compound of Example 109 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.5 Hz), 2.83 (2H, t, J=7.4 Hz), 3.10(2H, t, J=7.4 Hz), 3.74 (3H, s), 4.31 (1H, d, J=13.8 Hz), 4.45 (1H, d,J=13.2 Hz), 4.92 (1H, d, J=13.2 Hz), 5.15 (1H, s), 5.50 (1H, m), 5.60(1H, d, J=13.8 Hz), 5.96 (1H, d, J=8.1 Hz), 6.91 (2H, m), 7.10-7.23 (5H,m), 7.53 (1H, d, J=8.1 Hz).

MS: m/z=636.15 [M]⁺.

Example 110

According to Example 108, compound of Example 110 was synthesized by the

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.2 Hz), 2.22 (3H, s), 4.31 (1H, d,J=13.8 Hz), 4.46 (1H, d, J=13.4 Hz), 4.92 (1H, d, J=13.4 Hz), 5.05 (1H,d, J=16.5 Hz), 5.15 (1H, d, J=16.5 Hz), 5.15 (1H, s), 5.54 (1H, m), 5.60(1H, d, J=13.8 Hz), 5.97 (1H, d, J=8.1 Hz), 6.82-6.94 (2H, m), 7.09-7.23(5H, m), 7.54 (1H, d, J=8.1 Hz).

MS: m/z=622.15 [M]⁺.

Example 111

A dichloromethane (1.0 mL) solution of compound 98-a (50 mg, 0.10 mmol)was ice-cooled, triethylamine (0.040 ml, 0.29 mmol) and 2-methoxyacetylchloride (11 mg, 0.11 mmol) were added, and the mixture was stirred for1 hour under ice-cooling, then stirred at room temperature for 2 hours.Thereafter, to the reaction solution was added ethyl acetate, themixture was washed with water, and sodium sulfide was added to dry it.The solvent was distilled off, and a solid of the resulting oil wasprecipitated by using ethyl acetate to obtain 31 mg of compound ofExample 111 as a white solid.

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, 7.1 Hz), 3.59 (3H, s), 4.31 (1H, d,J=13.9 Hz), 4.41-4.54 (3H, m), 4.93 (1H, d, J=13.3 Hz), 5.16 (1H, s),5.46-5.63 (2H, m), 5.97 (1H, d, J=7.9 Hz), 6.90 (2H, brs), 7.09-7.24(5H, m), 7.53 (1H, d, J=7.4 Hz).

MS: m/z=594 [M+H]⁺.

Example 112

First Step

An acetonitrile (2 ml) solution of compound 106-a (100 mg, 0.231 mmol),chloromethyl pivalate (482 mg, 3.20 mmol) and sodium iodide (480 mg,3.20 mmol) was stirred at 80° C. for 6 hours. After cooled to roomtemperature, water was added, and the mixture was extracted with ethylacetate three times. The combined extracts were dried with sodiumsulfate, and the solvent was distilled off. The resulting oil waspurified by silica gel column chromatography. The materials were elutedfirstly with ethyl acetate and, then, with ethyl acetate-methanol (7:3,v/v). Concentration of an objective fraction afforded 35 mg of compoundof Example 112 as a solid.

¹H-NMR (CDCl₃) δ: 1.06 (3H, d, J=16.2 Hz), 10.9 (3H, d, J=9.3 Hz), 1.26(9H, s), 3.58 (1H, d, J=13.2 Hz), 4.29 (1H, d, J=13.2 Hz), 4.73-4.82(1H, m), 4.77 (1H, d, J=12.9 Hz), 5.10 (1H, s), 5.68 (2H, d, J=13.2 Hz),5.88-5.93 (3H, m), 6.86-6.88 (2H, m), 7.04-7.10 (2H, m), 7.15-7.27 (3H,m), 7.32-7.42 (2H, m).

Example 113

To an aqueous (0.5 mL) suspension of compound 113-a (50 mg, 0.10 mmol)and potassium carbonate (40 mg, 0.29 mmol) were added tetrabutylammoniumhydrogen sulfate (33 mg, 0.10 mmol) and dichloromethane (1.0 ml), andthe mixture was stirred at room temperature for 10 minutes. To thereaction solution was added a dichloromethane (1.0 ml) solution ofiodomethyl acetate (56 mg, 0.19 mmol), and the mixture was furtherstirred for 2 hours. Thereafter, to the reaction solution was addedwater, the dichloromethane layer was separated, and the aqueous layerwas extracted with dichloromethane once. The combined extracts werewashed with an aqueous saturated sodium chloride solution and brine, andthen sodium sulfide was added to dry them. The solvent was distilledoff, and the resulting oil was purified by silica gel columnchromatography. The materials were eluted firstly with chloroform and,then, with chloroform-methanol (94:6, v/v). An objective fraction wasconcentrated, and solidified by adding diisopropyl ether to obtain 41 mgof compound of Example 113 as a white solid.

¹H-NMR (DMSO-d6) δ: 0.98 (3H, d, J=7.2 Hz), 2.02 (3H, s), 3.98 (1H, d,J=7.2 Hz), 4.48 (1H, d, J=7.2 Hz), 5.05 (1H, d, J=7.2 Hz), 5.42-5.49(1H, m), 5.61 (1H, d, J=7.2 Hz), 5.66-5.77 (3H, m), 5.87 (1H, d, J=7.2Hz), 6.86-6.95 (2H, m), 7.16-7.20 (3H, m), 7.45-7.52 (3H, m).

MS: m/z=594 [M+H]⁺.

According to Example 113, the following compounds were synthesized bythe same procedure.

Example 114

¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.6 Hz), 1.09 (3H, d, J=6.6 Hz), 2.15(3H, s), 7.58 (1H, d, J=13.5 Hz), 4.30 (1H, d, J=12.9 Hz), 4.75-4.83(1H, m), 4.77 (1H, d, J=12.9 Hz), 5.12 (1H, s), 5.69 (d, J=13.5 Hz),5.82-5.92 (3H, m), 6.84-6.91 (2H, m), 7.04-7.08 (2H, m), 7.20-7.28 (3H,m), 7.32-7.42 (2H, m).

Example 115

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=7.3 Hz), 2.12 (3H, s), 3.90 (1H, d,J=14.7 Hz), 4.38 (1H, d, J=13.3 Hz), 4.91 (1H, d, J=13.3 Hz), 5.23 (1H,s), 5.57 (1H, m), 5.86 (1H, d, J=6.4 Hz), 5.86 (1H, d, J=14.7 Hz), 5.94(1H, d, J=7.8 Hz), 6.84 (1H, dd, J=1.2, 7.9 Hz), 6.91 (1H, dt, J=1.7,6.8 Hz), 7.09 (1H, dd, J=1.4, 7.6 Hz), 7.12 (1H, dd, J=1.4, 6.6 Hz),7.16 (1H, d, J=7.8 Hz), 7.6-7.42 (2H, m), 7.81 (1H, dd, J=2.1, 6.8 Hz).

MS: m/z=628 [M+H]⁺.

Example 116

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=7.2 Hz), 2.15 (3H, s), 4.26 (1H, d,J=13.9 Hz), 4.45 (1H, d, J=12.9 Hz), 4.92 (1H, d, J=13.3 Hz), 5.24 (1H,s), 5.45 (1H, dd, J=13.8, 1.9 Hz), 5.53-5.63 (1H, m), 5.89 (1H, d, J=6.4Hz), 5.95 (1H, d, J=6.4 Hz), 6.01 (1H, d, J=7.7 Hz), 6.84-7.34 (7H, m).

MS: m/z=612 [M+H]⁺.

Example 117

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=7.2 Hz), 2.10 (3H, s), 4.11 (1H, d,J=13.6 Hz), 4.42 (1H, d, J=13.1 Hz), 4.89 (1H, d, J=13.0 Hz), 5.13 (1H,s), 5.33 (1H, dd, J=13.6, 2.2 Hz), 5.55 (1H, m), 5.84-5.94 (3H, m),6.81-7.25 (8H, m).

Example 118

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.3 Hz), 2.11 (3H, s), 3.56 (1H, d,J=13.6 Hz), 4.42 (1H, d, J=13.0 Hz), 4.88 (1H, d, J=13.4 Hz), 5.10 (1H,s), 5.55 (1H, m), 5.67 (1H, d, J=13.4 Hz), 5.85-5.94 (3H, m), 6.81-7.26(8H, m).

MS: m/z=578 [M+H]⁺.

Example 119

MS: m/z=592 [M+H]⁺.

Example 120

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, 6.1 Hz), 2.10 (3H, s), 3.60 (1H, d, 13.4Hz), 4.42 (1H, d, J=13.0 Hz), 4.87 (1H, d, J=13.1 Hz), 5.07 (1H, s),5.48-5.64 (2H, m), 5.85-5.97 (3H, m), 6.80-6.89 (2H, m), 7.05-7.44 (7H,m).

MS: m/z=560 [M+H]⁺.

Example 121

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, 7.3 Hz), 2.10 (3H, s), 4.31 (1H, d, 13.9Hz), 4.42 (1H, d, J=13.3 Hz), 4.88 (1H, d, J=12.8 Hz), 5.12 (1H, s),5.50-5.62 (2H, m), 5.84-5.94 (3H, m), 6.80-6.91 (2H, m), 7.07-7.22 (5H,m), 7.52 (1H, d, J=7.6 Hz).

MS: m/z=594 [M+H]⁺.

Example 122

To an aqueous (1.0 mL) suspension of compound 122-a (50 mg, 0.10 mmol)and potassium carbonate (138 mg, 0.22 mmol) were addedtetrabutylammonium hydrogen sulfate (34 mg, 0.10 mmol) anddichloromethane (0.5 ml), and the mixture was stirred at roomtemperature for 10 minutes. To the reaction solution was added adichloromethane (0.5 ml) solution of iodomethyl 2-methoxyethyl carbonate(57 mg, 0.22 mmol), and the mixture was further stirred for 2 hours.Thereafter, to the reaction solution was added water, thedichloromethane layer was separated, and the aqueous layer was extractedwith dichloromethane once. The combined extracts were washed with anaqueous saturated sodium chloride solution and brine, and then sodiumsulfide was added to dry them. The solvent was distilled off, and theresulting oil was purified by silica gel column chromatography. Thematerials were eluted firstly with chloroform and, then, withchloroform-methanol (94:6, v/v). An objective fraction was concentrated,and washed using hexane-diethyl ether to obtain 39 mg of compound ofExample 122 as a white solid.

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=7.2 Hz), 3.38 (3H, s), 3.58-3.69 (3H,m), 4.28-4.44 (3H, m), 4.87 (1H, d, J=13.0 Hz), 5.09 (1H, s), 5.51-5.66(2H, m), 5.90-5.96 (3H, m), 6.84-7.44 (9H, m).

MS: m/z=620 [M+H]⁺.

Example 123

According to Example 122, compound of Example 123 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.32 (3H, d, J=7.3 Hz), 3.39 (3H, s), 3.59 (1H, d,J=13.3 Hz), 3.68-3.71 (2H, m), 4.39 (2H, dt, J=7.22, 2.14 Hz), 4.53 (1H,d, J=12.7 Hz), 4.92 (1H, d, J=12.7 Hz), 5.23-5.36 (2H, m), 5.67 (1H, d,J=13.2 Hz), 5.84 (1H, d, J=6.4 Hz), 5.92 (1H, d, J=6.5 Hz), 5.95 (1H, d,J=7.8 Hz), 6.83-7.41 (9H, m).

MS: m/z=620 [M+H]⁺.

Example 124

According to Example 122, compound of Example 124 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.10 (3H, d, J=7.3 Hz), 3.60 (1H, d, J=13.4 Hz), 3.75(2H, t, J=4.4 Hz), 4.33-4.42 (3H, m), 4.57 (2H, s), 4.85 (1H, d, J=13.6Hz), 5.07 (1H, s), 5.46-5.64 (2H, m), 5.90-5.96 (3H, m), 6.82-6.88 (2H,m), 7.06-7.43 (12H, m).

MS: m/z=696 [M+H]⁺.

Example 125

According to Example 122, compound of Example 125 was synthesized by the

¹H-NMR (CDCl₃) δ: 1.14 (3H, d, J=7.2 Hz), 3.61 (1H, d, J=13.4 Hz), 3.83(3H, s), 4.42 (1H, d, J=13.2 Hz), 4.87 (1H, d, J=13.0 Hz), 5.08 (1H, s),5.48-5.65 (2H, m), 5.87 (1H, d, J=6.5 Hz), 5.94 (1H, d, J=6.2 Hz), 5.96(1H, d, J=4.8 Hz), 6.79-6.85 (2H, m), 7.05-7.44 (7H, m).

MS: m/z=576 [M+H]⁺.

Example 126

According to Example 122, compound of Example 126 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, 6.0 Hz), 3.36 (3H, s), 3.52-3.79 (7H, m),4.31-4.44 (3H, m), 4.87 (1H, d, J=13.0 Hz), 5.09 (1H, s), 5.50-5.73 (2H,m), 5.89-5.98 (3H, m), 6.81-6.88 (2H, m), 7.05-7.45 (7H, m).

MS: m/z=664 [M+H]⁺.

Example 127

According to Example 122, compound of Example 127 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, 7.2 Hz), 3.37 (1H, s), 3.62-3.69 (2H, m),4.29-4.43 (4H, m), 4.88 (1H, d, J=13.6 Hz), 5.14 (1H, s), 5.50-5.63 (2H,m), 5.90-5.96 (3H, m), 6.82-6.89 (2H, m), 7.05-7.24 (5H, m), 7.52 (1H,d, J=7.9 Hz).

MS: m/z=654 [M+H]⁺.

Example 128

According to Example 122, compound of Example 128 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, 7.2 Hz), 3.83 (3H, s), 4.31 (1H, d,J=13.9 Hz), 4.42 (1H, d, J=13.1 Hz), 4.89 (1H, d, J=13.4 Hz), 5.12 (1H,s), 5.49-5.61 (2H, m), 5.87 (1H, d, J=6.5 Hz), 5.93-5.97 (2H, m),6.77-6.89 (2H, m), 7.09-7.24 (5H, m), 7.52 (1H, d, J=8.2 Hz).

MS: m/z=610 [M+H]⁺.

Example 129

According to Example 122, compound of Example 129 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, 7.3 Hz), 3.77 (3H, s), 4.31 (1H, d,J=14.0 Hz), 4.43 (11H, d, J=13.3 Hz), 4.60-4.70 (2H, m), 4.85-4.93 (2H,m), 5.31 (1H, s), 5.56-5.66 (2H, m), 5.93-6.01 (3H, m), 6.86-6.92 (2H,m), 7.08-7.51 (5H, m), 7.52 (1H, d, J=7.8 Hz).

MS: m/z=668 [M+H]⁺.

Example 130

According to Example 122, compound of Example 130 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.16-1.37 (3H, m), 2.77-2.87 (1H, m), 3.04-3.15 (1H,m), 3.41-3.53 (1H, m), 3.83-3.89 (3H, m), 4.24-4.42 (2H, m), 4.70-4.82(1H, m), 5.02-5.45 (2H, m), 5.82-5.99 (3H, m), 6.72-7.35 (9H, m).

MS: m/z=558 [M+H]⁺.

Example 131

According to Example 122, compound of Example 131 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, 7.2 Hz), 3.65 (1H, d, J=13.4 Hz), 3.83(3H, s), 4.41 (1H, d, 13.3 Hz), 4.88 (1H, d, J=13.4 Hz), 5.17 (1H, s),5.47-5.57 (1H, m), 5.68 (1H, d, J=13.4 Hz), 5.87 (1H, d, J=6.6 Hz),5.95-6.00 (2H, m), 6.65 (1H, d, J=7.3 Hz), 6.83-6.99 (3H, m), 7.01-7.20(3H, m).

MS: m/z=612 [M+H]⁺.

Example 132

According to Example 122, compound of Example 132 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.12 (3H, d, 7.2 Hz), 3.62 (1H, d, J=13.3 Hz), 3.83(3H, s), 4.40 (1H, d, 12.9 Hz), 4.86 (1H, d, J=12.7 Hz), 5.06 (1H, s),5.48-5.62 (2H, m), 5.88 (1H, d, J=6.5 Hz), 5.97 (1H, d, J=6.6 Hz), 6.02(1H, d, J=7.8 Hz), 6.75-6.85 (2H, m), 7.08-7.43 (6H, m).

MS: m/z=610 [M+H]⁺.

Example 133

According to Example 122, compound of Example 133 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.11 (3H, d, 7.1 Hz), 3.68 (1H, d, J=13.4 Hz), 3.84(3H, s), 4.43 (1H, d, 13.5 Hz), 4.88 (1H, d, J=12.8 Hz), 5.16 (1H, s),5.47-5.64 (2H, m), 5.90 (1H, d, J=6.4 Hz), 5.95-5.99 (2H, m), 7.00 (1H,d, J=7.7 Hz), 7.11-7.49 (8H, m).

MS: m/z=644 [M+H]⁺.

Example 134

According to Example 122, compound of Example 134 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.19-1.35 (3H, m), 2.77-2.89 (1H, m), 3.04-3.14 (1H,m), 3.37-3.51 (1H, m), 3.83-3.89 (3H, m), 4.27-4.41 (2H, m), 4.71-4.82(1H, m), 5.03-5.52 (2H, m), 5.89-6.00 (3H, m), 6.68-7.19 (7H, m).

MS: m/z=594 [M+H]⁺.

Example 135

According to Example 122, compound of Example 135 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, 7.4 Hz), 3.83 (3H, s), 4.37-4.43 (2H, m),4.89 (1H, d, J=12.9 Hz), 5.19 (1H, s), 5.49-5.64 (2H, m), 5.87 (1H, d,J=6.5 Hz), 5.95-6.00 (2H, m), 6.65 (1H, d, J=7.3 Hz), 7.07-7.25 (4H, m),7.54 (1H, d, J=7.0 Hz).

MS: m/z=628 [M+H]⁺.

Example 136

According to Example 122, compound of Example 136 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, 7.0 Hz), 3.61 (1H, d, J=13.7 Hz), 3.83(3H, s), 4.40 (1H, d, J=13.0 Hz), 4.86 (1H, d, J=13.5 Hz), 5.08 (1H, s),5.49-5.65 (2H, m), 5.88 (1H, d, J=6.5 Hz), 5.95-6.02 (2H, m), 6.53-6.60(1H, m), 6.79-6.84 (2H, m), 7.14-7.43 (5H, m).

MS: m/z=594 [M+H]⁺.

Example 137

According to Example 122, compound of Example 137 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, 7.2 Hz), 3.38 (3H, s), 3.60-3.68 (3H, m),4.28-4.39 (3H, m), 4.85 (1H, d, J=13.0 Hz), 5.48-5.57 (1H, m), 5.65 (1H,d, J=13.6 Hz), 5.87-5.98 (4H, m), 6.87-6.96 (2H, m), 7.07-7.17 (3H, m),7.25-7.34 (3H, m).

MS: m/z=654 [M+H]⁺.

Example 138

According to Example 122, compound of Example 138 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, 7.4 Hz), 1.81 (2H, brs), 2.02 (2H, brs),3.54-3.62 (2H, m), 3.91-3.99 (3H, m), 4.31 (1H, d, J=13.7 Hz), 4.42 (1H,d, J=12.9 Hz), 4.86-4.92 (2H, m), 5.11 (1H, s), 5.45-5.61 (2H, m),5.90-5.95 (3H, m), 6.71-6.87 (2H, m), 7.03-7.25 (5H, m), 7.52 (1H, d,J=6.9 Hz).

MS: m/z=680 [M+H]⁺.

Example 139

According to Example 122, compound of Example 139 was synthesized by thesame procedure.

MS: m/z=720 [M+H]⁺.

Example 140

Compound of Example 140 was obtained as a by-product of Example 139.

MS: m/z=606 [M+H]⁺.

Example 141

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.2 Hz), 3.84 (3H, s), 3.99 (1H, d,J=14.7 Hz), 4.39 (1H, d, J=13.2 Hz), 4.92 (1H, d, J=13.2 Hz), 5.23 (1H,s), 5.55 (1H, m), 5.8-6.0 (4H, m), 6.7-7.0 (2H, m), 7.0-7.3 (3H, m),7.3-7.5 (2H, m), 7.81 (1H, dd, J=6.3 Hz, J=2.7 Hz)

MS: m/z=644 [M+H]⁺.

Example 142

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.5 Hz), 3.85 (3H, s), 4.24 (1H, d,J=13.8 Hz), 4.43 (1H, d, J=13.2 Hz), 4.91 (1H, d, J=13.2 Hz), 5.23 (1H,s), 5.43 (1H, d, J=13.8 Hz), 5.54 (1H, m), 5.8-6.1 (3H, m), 6.7-7.1 (3H,m), 7.1-7.4 (4H, m) MS: m/z=628 [M+H]⁺.

Example 143

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=7.5 Hz), 2.25 (3H, s), 3.83 (3H, s),4.21 (1H, d, J=13.8 Hz), 4.43 (1H, d, J=13.5 Hz), 4.90 (1H, d, J=13.5Hz), 5.17 (1H, s), 5.37 (1H, d, J=15.6 Hz), 5.53 (1H, m), 5.8-6.0 (3H,m), 6.6-6.8 (2H, m), 6.9-7.1 (2H, m), 7.1-7.3 (3H, m)

MS: m/z=608 [M+H]⁺.

Example 144

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=6.9 Hz), 3.84 (3H, s), 4.12 (1H, d,J=13.8 Hz), 4.42 (1H, d, J=13.2 Hz), 4.90 (1H, d, J=13.2 Hz), 5.14 (1H,s), 5.34 (1H, d, J=13.8 Hz), 5.54 (1H, m), 5.8-6.0 (3H, m), 6.7-6.9 (2H,m), 6.9-7.1 (3H, m), 7.1-7.3 (3H, m)

MS: m/z=594 [M+H]⁺.

Example 145

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.5 Hz), 3.56 (1H, d, J=13.5 Hz), 3.84(3H, s), 4.42 (1H, d, J=13.2 Hz), 4.89 (1H, d, J=13.2 Hz), 5.10 (1H, s),5.53 (1H, m), 5.66 (1H, d, J=13.5 Hz), 5.8-6.0 (3H, m), 6.7-7.0 (3H, m),7.0-7.3 (5H, m)

MS: m/z=594 [M+H]⁺.

Example 146

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, J=7.2 Hz), 3.63 (1H, d, J=12.6 Hz), 3.83(3H, s), 4.39 (1H, d, J=13.2 Hz), 4.86 (1H, d, J=13.2 Hz), 5.23 (1H, m),5.65 (1H, d, J=13.5 Hz), 5.8-6.0 (4H, m), 6.8-7.0 (2H, m), 7.0-7.2 (3H,m), 7.2-7.4 (3H, m) MS: m/z=610 [M+H]⁺.

Example 147

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, J=6.0 Hz), 1.34 (3H, t, J=7.1 Hz), 3.65(1H, m), 4.29 (3H, m), 4.42 (1H, d, J=13.5 Hz), 4.90 (1H, d, J=13.5 Hz),5.13 (1H, s), 5.58 (2H, m), 5.92 (3H, m), 6.82 (2H, m), 7.00-7.26 (5H,m), 7.53 (1H, d, J=8.4 Hz).

MS: m/z=624.15 [M]⁺.

Example 148

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.2 Hz), 1.34 (3H, t, J=6.3 Hz), 1.35(3H, t, J=6.3 Hz), 4.32 (1H, d, J=13.7 Hz), 4.42 (1H, d, J=13.1 Hz),4.89 (1H, d, J=13.1 Hz), 4.96 (1H, m), 5.13 (1H, s), 5.54 (1H, m), 5.60(1H, d, J=13.7 Hz), 5.87 (1H, d, J=6.8 Hz), 5.95 (2H, d, J=6.9 Hz), 6.85(2H, m), 7.06-7.26 (5H, m), 7.53 (1H, d, J=6.8 Hz).

MS: m/z=638.15 [M]⁺.

Example 149

MS: m/z=628.35 [M]P

Example 150

MS: m/z=594.15 [M]⁺.

Example 151

According to Example 122, compound 151-a was synthesized by the sameprocedure.

To an ethyl acetate (2.0 mL) solution of compound 151-a (67 mg, 0.093mmol) was added a 4N HCl ethyl acetate solution (2.0 ml), and themixture was stirred at room temperature overnight. Thereafter, to thereaction solution were added ethyl acetate and water, the ethyl acetatelayer was separated, and the aqueous layer was extracted with ethylacetate two times. To the combined extracts was added sodium sulfide,and the mixture was dried, then the solvent was distilled off. To theresulting oil was added diisopropyl ether, and the precipitated solidwas filtered to obtain 12 mg of compound of Example 151 as a whitesolid.

¹H-NMR (CDCl₃) δ: 1.24 (3H, d, 6.8 Hz), 2.80 (2H, brs), 4.31 (1H, d,J=13.7 Hz), 4.40-4.51 (3H, m), 4.86 (2H, m), 4.86 (1H, d, 13.1 Hz), 5.21(1H, s), 5.53-5.62 (2H, m), 5.83-5.93 (3H, m), 6.75-6.86 (2H, m),7.09-7.25 (5H, m), 7.48 (1H, d, J=9.0 Hz).

MS: m/z=668 [M+H]⁺.

Example 152

Compound 98-a (43 mg, 0.29 mmol) and silver(I) oxide (44 mg, 0.10 mmol)were added to an acetonitrile (1.5 mL) solution of 1-chloroethyl methylcarbonate (166 mg, 0.96 mmol), and the mixture was stirred at 50° C. for4 hours, and then allowed to stand at room temperature overnight.Thereafter, the reaction solution was filtered with celite, the solventwas distilled off, and the resulting oil was purified by silica gelcolumn chromatography. The materials were eluted firstly with chloroformand, then, with chloroform-methanol (95:5, v/v). An objective fractionwas concentrated, and washed using hexane-diisopropyl ether to obtain 54mg of compound of Example 152 as a white solid.

¹H-NMR (CDCl₃) δ: 1.14-1.16 (3H, m), 1.82-1.85 (3H, m), 3.66-3.83 (3H,m), 4.27-4.43 (2H, m), 4.82-4.91 (1H, m), 5.10-5.12 (1H, m), 5.54-5.62(2H, m), 5.89-5.93 (1H, m), 6.52-6.56 (1H, m), 6.75-6.98 (2H, m),7.07-7.21 (5H, m), 7.52 (1H, d, J=8.1 Hz).

MS: m/z=624 [M+H]⁺.

Example 153

According to Example 152, compound of Example 153 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.14-1.16 (3H, m), 1.21-1.41 (3H, m), 1.84 (3H, d,J=5.1 Hz), 4.02-4.43 (4H, m), 4.83-4.89 (1H, m), 5.09-5.11 (1H, m),5.54-5.61 (2H, m), 5.88-5.92 (1H, m), 6.48-6.55 (1H, m), 6.75-7.21 (7H,m), 7.51 (1H, d, J=8.2 Hz).

MS: m/z=638 [M+H]⁺.

Example 154

According to Example 152, compound of Example 154 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.10-1.43 (9H, m), 1.83 (3H, d, J=5.3 Hz), 4.27-4.43(2H, m), 4.67-4.90 (2H, m), 5.08-5.12 (1H, m), 5.54-5.60 (2H, m),5.86-5.91 (1H, m), 6.43-6.57 (1H, m), 6.71-7.20 (7H, m), 7.51 (1H, d,J=8.1 Hz).

MS: m/z=652 [M+H]⁺.

Example 155

According to Example 152, compound of Example 155 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.12-1.15 (3H, m), 1.82-1.85 (3H, m), 3.66-3.84 (3H,m), 4.08-4.14 (1H, m), 4.37-4.44 (1H, m), 4.82-4.92 (1H, m), 5.12-5.14(1H, m), 5.28-5.32 (1H, m), 5.52-5.60 (1H, m), 5.89-5.93 (1H, m),6.51-6.55 (1H, m), 6.77-7.24 (8H, m).

MS: m/z=608 [M+H]⁺.

Example 156

According to Example 152, compound of Example 156 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.10-1.14 (3H, m), 1.82-1.84 (3H, m), 3.65-3.83 (3H,m), 4.17-4.23 (1H, m), 4.36-4.42 (1H, m), 4.82-4.90 (1H, m), 5.17-5.19(1H, m), 5.35-5.58 (2H, m), 5.92-5.96 (1H, m), 6.49-6.53 (1H, m),6.71-7.14 (4H, m), 7.21-7.29 (3H, m).

MS: m/z=642 [M+H]⁺.

Example 157

According to Example 152, compound of Example 157 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.12-1.15 (3H, m), 1.82-1.85 (3H, m), 3.51-3.55 (1H,m), 3.66-3.83 (3H, m), 4.37-4.43 (1H, m), 4.81-4.89 (1H, m), 5.07-5.09(1H, m), 5.53-5.68 (2H, m), 5.88-5.91 (1H, m), 6.51-6.56 (1H, m),6.76-7.00 (3H, m), 7.06-7.18 (5H, m).

MS: m/z=608 [M+H]⁺.

Example 158

According to Example 152, compound of Example 158 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.10-1.14 (3H, m), 1.81-1.84 (3H, m), 2.24-2.25 (3H,m), 3.65-3.83 (3H, m), 4.17-4.23 (1H, m), 4.38-4.43 (1H, m), 4.82-4.90(1H, m), 5.14-5.16 (1H, m), 5.31-5.38 (1H, m), 5.51-5.60 (1H, m),5.86-5.90 (1H, m), 6.51-6.56 (1H, m), 6.65-7.23 (7H, m).

MS: m/z=622 [M+H]⁺.

Example 159

According to Example 152, compound of Example 159 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.10-1.16 (3H, m), 1.63-2.02 (7H, m), 3.44-4.04 (4H,m), 4.27-4.44 (2H, m), 4.62-4.90 (2H, m), 5.05-5.13 (1H, m), 5.49-5.61(2H, m), 5.87-5.91 (1H, m), 6.44-6.58 (1H, m), 6.78-7.26 (7H, m), 7.53(1H, d, J=7.8 Hz).

MS: m/z=694 [M+H]⁺.

Example 160

According to Example 152, compound of Example 160 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.12-1.15 (3H, m), 1.82-1.85 (3H, m), 3.66-3.84 (3H,m), 3.94-4.00 (1H, m), 4.33-4.39 (1H, m), 4.84-4.92 (1H, m), 5.20-5.21(1H, m), 5.52-5.62 (1H, m), 5.80-5.93 (2H, m), 6.51-6.56 (1H, m),6.71-7.14 (5H, m), 7.36-7.38 (2H, m), 7.78-7.81 (1H, m).

MS: m/z=658 [M+H]⁺.

Example 161

¹H-NMR (CDCl₃) δ: 1.05 (6H, m), 1.19-1.27 (3H, m), 1.34-1.45 (3H, m),1.82-1.87 (3H, m), 2.80 (1H, ddd, J=4.2 Hz, 4.2 Hz, 13.8 Hz), 4.02-3.14(1H, m), 3.43-3.52 (1H, m), 4.15-4.21 (1H, m), 4.25-4.38 (1H, m),4.59-4.77 (2H, m), 5.05 (1H, d, J=11.7 Hz), 5.76-5.81 (1H, m), 6.45-6.51(1H, m), 6.64-6.67 (1H, m), 6.79 (0.5H, d, J=7.5 Hz), 6.90-7.35 (6.5H,m).

Example 162

According to Example 152, compound of Example 162 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.10 (3H, d, 7.3 Hz), 1.84 (3H, d, 5.2 Hz), 3.60 (1H,d, 13.5 Hz), 3.65 (3H, s), 4.41 (1H, d, J=13.0 Hz), 4.87 (1H, d, J=12.7Hz), 5.06 (1H, s), 5.52-5.62 (2H, m), 5.91 (1H, d, J=7.8 Hz), 6.53 (1H,q, J=5.3), 6.76-6.84 (2H, m), 7.06-7.43 (7H, m).

MS: m/z=590 [M+H]⁺.

Example 163

According to Example 122, compound 163-a was synthesized by the sameprocedure.

To an acetonitrile (1.0 mL) solution of compound 163-a (70 mg, 0.10mmol) and potassium carbonate (138 mg, 0.22 mmol) were added2-morpholinoethanamine (31 mg, 0.24 mmol), DMAP (13 mg, 0.10 mmol) andtriethylamine (0.042 ml, 0.30 mmol), and the mixture was stirred at roomtemperature overnight. Thereafter, to the reaction solution was addedwater, the dichloromethane layer was separated, and the aqueous layerwas extracted with dichloromethane once. The combined extracts werewashed with an aqueous saturated sodium chloride solution and brine, andthen sodium sulfide was added to dry them. The solvent was distilledoff, and the resulting oil was purified by silica gel columnchromatography. The materials were eluted firstly with chloroform and,then, with chloroform-methanol (94:6, v/v). An objective fraction wasconcentrated, and washed using diisopropyl ether to obtain 26 mg ofcompound of Example 163 as a yellowish-white solid.

MS: m/z=674 [M+H]⁺.

Example 164

According to Example 163, compound of Example 164 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, 7.0 Hz), 1.33-1.36 (6H, m), 3.61 (1H, d,J=13.4 Hz), 4.42 (1H, d, J=13.3 Hz), 4.85-4.99 (2H, m), 5.08 (1H, s),5.49-5.64 (2H, m), 5.86 (1H, d, J=6.4 Hz), 5.93-5.97 (2H, m), 6.82-6.88(2H, m), 7.05-7.44 (7H, m).

MS: m/z=604 [M+H]⁺.

Example 165

According to Example 163, compound of Example 165 was synthesized by thesame procedure.

MS: m/z=675 [M+H]⁺.

Example 166

According to Example 163, compound of Example 166 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.12 (3H, d, 7.3 Hz), 2.78 (3H, d, J=5.0), 3.60 (1H,d, J=13.1 Hz), 4.42 (1H, d, J=13.3 Hz), 4.78 (1H, brs), 4.87 (1H, d,J=12.9 Hz), 5.09 (1H, s), 5.54-5.64 (2H, m), 5.84-5.94 (3H, m),6.83-6.89 (2H, m), 7.07-7.44 (7H, m).

MS: m/z=575 [M+H]⁺.

Example 167

According to Example 163, compound of Example 167 was synthesized by thesame procedure.

MS: m/z=675 [M+H]⁺.

Example 168

According to Example 163, compound of Example 168 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.12 (3H, d, 7.4 Hz), 3.35-3.38 (5H, m), 3.46 (2H, t,J=5.1 Hz), 3.60 (1H, d, J=13.4 Hz), 4.42 (1H, d, J=13.1), 4.87 (1H, d,J=12.4 Hz), 5.09-5.16 (2H, m), 5.87-5.94 (3H, m), 6.81-6.89 (2H, m),7.05-7.45 (7H, m).

MS: m/z=619 [M+H]⁺.

Example 169

According to Example 163, compound of Example 169 was synthesized by thesame procedure.

MS: m/z=673 [M+H]⁺.

Example 170

According to Example 163, compound of Example 170 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.12 (3H, d, 7.3 Hz), 3.48-3.77 (9H, m), 4.42 (1H, d,J=13.4 Hz), 4.87 (1H, d, J=13.4), 5.07 (1H, s), 5.49-5.63 (2H, m),5.91-5.94 (3H, m), 6.84-6.86 (2H, m), 7.06-7.45 (7H, m).

MS: m/z=631 [M+H]⁺.

Example 171

According to Example 163, compound of Example 171 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, 7.3 Hz), 4.31 (1H, d, J=13.9 Hz), 4.42(1H, d, J=13.2 Hz), 4.72 (2H, brs), 4.89 (1H, d, J=12.8 Hz), 5.14 (1H,s), 5.55-5.62 (2H, m), 5.87 (2H, s), 5.94 (1H, d, J=7.8 Hz), 6.81-6.89(2H, m), 7.07-7.21 (5H, m), 7.52 (1H, d, J=7.1 Hz).

MS: m/z=595 [M+H]⁺.

Example 172

According to Example 163, compound of Example 172 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, 7.8 Hz), 2.89 (3H, s), 2.95 (3H, s), 4.31(1H, d, J=14.0 Hz), 4.41 (1H, d, J=13.5 Hz), 4.89 (1H, d, J=13.3 Hz),5.13 (1H, s), 5.52-5.61 (2H, m), 5.85-5.96 (3H, m), 6.83-6.88 (2H, m),7.07-7.22 (5H, m), 7.52 (1H, d, J=7.0 Hz).

MS: m/z=623 [M+H]⁺.

Example 173

According to Example 163, compound of Example 173 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.33 (3H, d, 7.4 Hz), 3.37-3.62 (8H, m), 4.52 (1H, d,J=12.4 Hz), 4.92 (1H, d, J=12.4 Hz), 5.23-5.30 (3H, m), 5.65 (1H, d,13.0 Hz), 5.80-5.95 (3H, m), 6.84-6.91 (2H, m), 7.03-7.09 (2H, m),7.18-7.41 (5H, m).

MS: m/z=619 [M+H]⁺.

Example 174

According to Example 163, compound of Example 174 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.38 (3H, d, 7.2 Hz), 2.92 (1H, d, 4.5 Hz), 3.10 (1H,d, 4.5 Hz), 3.45 (2H, brs), 4.34 (1H, d, J=14.3 Hz), 4.52-4.57 (2H, m),4.90 (1H, d, J=13.8 Hz), 5.10 (1H, brs), 5.52-5.60 (3H, m), 5.75 (1H, d,J=6.9 Hz), 6.02 (1H, d, J=6.8 Hz), 6.85-6.96 (3H, m), 7.07-7.28 (3H, m),7.50-7.57 (2H, m), 7.73 (1H, d, J=7.4 Hz).

MS: m/z=667 [M+H]⁺.

Example 175

According to Example 163, compound of Example 175 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, 7.3 Hz), 2.01 (3H, s), 3.19-3.45 (4H, m),4.32 (1H, d, 14.0 Hz), 4.46 (1H, d, J=13.2 Hz), 4.90 (1H, d, J=13.1 Hz),5.17-5.19 (2H, m), 5.53-5.68 (3H, m), 5.89-5.97 (2H, m), 6.87-6.95 (2H,m), 7.08-7.26 (5H, m), 7.54 (1H, d, J=7.8 Hz).

MS: m/z=680 [M+H]⁺.

Example 176

According to Example 163, compound of Example 176 was synthesized by thesame procedure.

MS: m/z=666 [M+H]⁺.

Example 177

According to Example 163, compound 177-a was synthesized by the sameprocedure.

To an ethyl acetate solution (2.0 mL) solution of compound 177-a (129mg, 0.17 mmol) was added a 4N HCl ethyl acetate solution (2.0 ml), andthe mixture was stirred at room temperature for 30 minutes. Thereafter,to the reaction solution was added water, the ethyl acetate layer wasseparated, and the aqueous layer was extracted with ethyl acetate twotimes. The combined extracts were washed with an aqueous saturatedsodium chloride solution and brine, and then sodium sulfide was added todry them. The solvent was distilled off, and the resulting oil waspurified by silica gel column chromatography. The materials were elutedfirstly with chloroform and, then, with chloroform-methanol (94:6, v/v).An objective fraction was concentrated, and washed using diisopropylether to obtain 10 mg of compound of Example 177 as a pale pink solid.

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, 7.2 Hz), 3.61 (1H, d, 13.4 Hz), 3.92 (2H,brs), 4.30-4.51 (3H, m), 4.86 (1H, d, J=12.8), 5.09 (1H, s), 5.44-5.62(2H, m), 5.86 (1H, d, J=6.6 Hz), 5.94-5.97 (2H, m), 6.88-6.90 (2H, m),7.08-7.44 (7H, m).

MS: m/z=606 [M+H]⁺.

Example 178

According to Example 163, compound 178-a was synthesized by the sameprocedure.

To an ethyl acetate solution (1.0 mL) solution of compound 178-a (81 mg,0.11 mmol) was added a 4N HCl ethyl acetate solution (1.0 ml), and themixture was stirred at room temperature for 1 hour and 30 minutes. Asolid precipitated from the reaction solution was filtered, and washedwith diisopropyl ether to obtain 54 mg of compound of Example 178 as awhite solid.

MS: m/z=638 [M+H]⁺.

Example 179

A DMF (1 ml) solution of compound 179-a (50 mg, 0.120 mmol) andtriethylamine (61 mg, 0.60 mmol) was cooled to 1 to 3° C., and ethylchloroformate (26 mg, 0.24 mmol) was added dropwise while the sametemperature was retained. After the reaction solution was stirred atroom temperature for 30 minutes, water was added, and the mixture wasextracted with ethyl acetate three times. The extract was washed withwater three times, and dried with sodium sulfate, then the solvent wasdistilled off. The resulting solid was washed with ethyl-diisopropylether to obtain 24 mg of compound of Example 179.

¹H-NMR (CDCl₃) δ: 1.11 (3H, d, J=6.9 Hz), 1.12 (3H, d, J=6.9 Hz), 1.44(3H, t, J=6.9 Hz), 2.82 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 3.09 (1H,ddd, J=3.9H, 13.5 Hz, 13.5 Hz), 3.49 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.4Hz), 4.24 (1H, d, 13.2 Hz), 4.29-4.43 (2H, m), 4.40 (1H, d, J=7.2 Hz),4.66-4.77 (1H, m), 4.69 (1H, d, J=12.9 Hz), 5.10 (1H, s), 5.87 (1H, d,J=8.1 Hz), 6.77 (1H, d, J=7.8 Hz), 6.79-6.82 (1H, m), 6.98 (1H, t, J=7.2Hz), 7.07-7.37 (6H, m).

According to Example 179, the following compounds of Examples weresynthesized by the same procedure.

Example 180

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=7.2 Hz), 3.98 (3H, s), 4.31 (1H, d,J=13.8 Hz), 4.46 (1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 5.16 (1H,s), 5.48-5.57 (1H, m), 5.60 (1H, d, J=14.1 Hz), 5.99 (1H, d, J=7.8 Hz),6.23-6.93 (2H, m), 7.07-7.25 (6H, m), 7.51-7.54 (1H, m).

Example 181

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=7.2 Hz), 3.45 (3H, s), 3.74 (2H, t,J=5.1 Hz), 4.31 (1H, d, J=13.8 Hz), 4.43-4.48 (3H, m), 4.93 (1H, d,J=13.2 Hz), 5.16 (1H, s), 5.48-5.57 (1H, m), 5.60 (1H, d, J=14.1 Hz),5.98 (1H, d, J=7.8 Hz), 6.82-6.92 (2H, m), 7.06-7.12 (3H, m), 7.14-7.25(2H, m), 7.52 (1H, d, J=8.1 Hz).

Example 182

¹H-NMR (CDCl₃) δ: 1.22 (3H, d, J=7.2 Hz), 4.31 (1H, d, J=13.8 Hz), 4.48(1H, d, J=13.2 Hz), 4.95 (1H, d, J=13.2 Hz), 5.17 (1H, s), 5.53-5.63(2H, m), 6.02 (1H, d, J=7.8 Hz), 6.83-6.88 (2H, m), 7.06-7.13 (3H, m),7.17-7.39 (3H, m), 7.41-7.51 (4H, m), 7.51-7.55 (1H, m).

Example 183

¹H-NMR (CDCl₃) δ: 1.04 (6H, d, J=6.6 Hz), 1.19 (3H, d, J=7.2 Hz),2.08-2.17 (1H, m), 4.11 (2H, d, J=6.6 Hz), 4.31 (1H, d, J=13.8 Hz), 4.46(1H, d, J=13.5 Hz), 4.93 (11H, d, J=12.9 Hz), 5.16 (1H, s), 5.48-5.62(2H, m), 5.98 (1H, d, J=8.1 Hz), 6.82-6.92 (2H, m), 7.07-7.26 (5H, m),7.51-7.55 (1H, m).

Example 184

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=7.2 Hz), 1.60 (9H, s), 4.31 (1H, d,J=13.8 Hz), 4.45 (1H, d, J=13.2 Hz), 4.92 (1H, d, J=13.2 Hz), 5.17 (1H,s), 5.48-5.63 (2H, m), 5.97 (1H, d, J=7.5 Hz), 6.81-6.92 (2H, m),7.07-7.14 (3H, m), 7.17-7.22 (2H, m), 7.12-7.54 (1H, m).

Example 185

¹H-NMR (DMSO-d₆) δ: 1.01 (6H, t, J=7.17 Hz), 1.31 (3H, t, J=7.09 Hz),3.88 (1H, d, J=13.27 Hz), 4.20-4.30 (3H, m), 4.61 (1H, t, J=6.71 Hz),5.00 (1H, d, J=13.42 Hz), 5.32 (1H, s), 5.65 (1H, d, J=13.27 Hz), 5.87(1H, d, J=7.78 Hz), 6.82-6.93 (2H, m), 7.06-7.15 (2H, m), 7.22-7.50 (5H,m).

MS: m/z=505.95 [M+H]⁺.

Example 186

According to the method shown in Journal of Medicinal Chemistry;English; 39; 2; 1996; 480-486, to a DMF (1 ml) solution of compound 98-a(50 mg, 0.0958 mmol) and triethylamine (48 mg, 0.48 mmol) were added(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate (85 mg,0.29 mmol) and DMAP (1.2 mg, 0.096 mmol) at room temperature, and themixture was stirred at the same temperature for 6 hours. The reactionsolution was diluted with ethyl acetate (10 ml), and water was added.The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate once. The extract was washed with water three times,and dried with sodium sulfate, and the solvent was distilled off. Theresulting crude product was purified by silica gel columnchromatography. The materials were eluted firstly with ethyl acetateand, then, with ethyl acetate-methanol (4:1, v/v). Concentration of anobjective fraction afforded 31 mg of compound of Example 186 as a solid.

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=7.2 Hz), 2.27 (3H, s), 4.33 (1H, d,J=14.1 Hz), 4.47 (1H, d, J=13.5 Hz), 4.91 (2H, d, J=13.2 Hz), 5.18 (1H,d, J=17.7 Hz), 5.21 (1H, s), 5.38-5.49 (1H, m), 5.58 (1H, d, J=13.8 Hz),6.01 (1H, d, J=7.8 Hz), 6.83-6.89 (2H, m), 7.08-7.15 (2H, m), 7.18-7.27(3H, m), 7.51-7.54 (1H, m).

According to Example 186, the following compounds were synthesized bythe same procedure.

Example 187

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=7.2 Hz), 1.87-2.01 (2H, m), 2.06-2.17(2H, m), 3.57-3.64 (2H, m), 3.98-4.04 (2H, m), 4.32 (1H, d, J=14.1 Hz),4.46 (1H, d, J=13.2 Hz), 4.92-5.02 (2H, m), 5.16 (1H, s), 5.46-5.58 (1H,m), 6.60 (1H, d, J=14.1 Hz), 5.99 (1H, d, J=8.1 Hz), 6.81-6.93 (2H, m),7.08-7.28 (4H, m), 7.54 (1H, d, J=6.6 Hz).

Example 188

¹H-NMR (CDCl₃) δ: 1.12-1.27 (12H, m), 3.55-3.66 (5H, m), 3.73-3.79 (4H,m), 4.31 (1H, d, J=13.8 Hz), 4.45 (1H, d, J=13.2 Hz), 4.93 (1H, d,J=13.2 Hz), 5.03-5.06 (1H, m), 5.16 (1H, s), 5.46-5.62 (2H, m),5.95-6.00 (1H, m), 6.85-6.92 (2H, m), 7.07-7.26 (5H, m), 7.53 (1H, d,J=7.8 Hz).

Example 189

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, J=7.2 Hz), 2.94 (3H, s), 4.32 (1H, d,J=13.8 Hz), 4.46 (1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.8 Hz), 5.16 (1H,s), 5.51-5.62 (2H, m), 5.98 (1H, d, J=7.8 Hz), 6.82-6.84 (1H, m),6.88-6.93 (1H, m), 7.07-7.12 (3H, m), 7.14-7.26 (3H, m), 7.51-7.54 (1H,m).

Example 190

Compound 106-a (80.0 mg, 0.185 mmol) was dissolved in dichloromethane (1ml), triethylamine (0.051 ml, 0.37 mmol), dimethylcarbamic chloride(39.7 mg, 0.369 mmol), and DMAP (cat.) were added, and the mixture wasstirred at 50° C. for 3 hours. To the reaction solution was added water,the mixture was extracted with ethyl acetate, and the organic layer waswashed with water, and dried with sodium sulfate. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas purified by silica gel column chromatography, and eluted withchloroform-methanol (97:3, v/v). Dichloromethane-ethyl acetate-diethylether were added, and the mixture was solidified to obtain 47 mg ofcompound of Example 190 as a white solid.

MS: m/z=505 [M+H]⁺.

Example 191

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=7.2 Hz), 2.96 (3H, d, J=5.1 Hz), 4.30(1H, d, J=13.8 Hz), 4.45 (1H, d, J=13.2 Hz), 4.92 (1H, d, J=12.9 Hz),5.20 (1H s), 5.29-5.30 (1H, m), 5.48-5.58 (1H, m), 5.60 (1H, d, J=13.8Hz), 5.96 (1H, d, J=13.8 Hz), 6.91-6.92 (2H, m), 7.06-7.21 (5H, m),7.50-7.53 (1H, m).

Example 192

First Step

According to the method described in Chem. Pharm. Bull. 55, 328-333(2007), compound 192-b was synthesized.

Second Step

To a pyridine (1 mL) solution of compound 192-b (78.0 mg, 0.273 mmol)was added compound 98-a (51.0 mg, 0.098 mmol), and the mixture wasstirred at room temperature for 1.5 hours, at 50° C. for 3 hours, and70° C. for 7 hours. The reaction solution was diluted with ethyl acetate(10 mL), the mixture was washed with water (5 mL) and hydrochloric acid(2M, 5 mL), and the organic layer was dried with sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingcrude product of compound 192-c was used in a next reaction withoutpurification.

Third Step

To an ethanol (0.5 mL) solution of the crude product of compound 192-cobtained in the second step was added concentrated hydrochloric acid(0.050 ml) at room temperature, and the mixture was stirred for 2 hours.To the reaction solution was added water (20 mL), and the mixture wasextracted with chloroform, then the organic layer was dried with sodiumsulfate. The solvent was distilled off under reduced pressure, and theresulting residue was purified by silica gel column chromatography(ethyl acetate/n-hexane=80%→100%), and the resulting product wasconverted into a powder with ethyl acetate-ethyl ether to obtaincompound of Example 192 (39.7 mg, 65%) as a white solid.

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=6.9 Hz), 3.02-3.70 (5H, m), 3.80-4.25(4H, m), 4.32 (1H, m), 4.47 (1H, d, J=13.2 Hz), 4.94 (1H, m), 5.18 (1H,m), 5.30 (1H, m), 5.60 (1H, d, J=13.8 Hz), 5.97 (1H, m), 6.75-7.25 (5H,m), 7.52 (1H, d, J=7.8 Hz).

MS: m/z=623.15 [M]⁺.

Example 193

According to Example 192, compound of Example 193 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=8.1 Hz), 1.80-2.20 (4H, m), 3.50-4.20(6H, m), 4.20-4.80 (3H, m), 4.92 (1H, m), 5.19 (1H, m), 5.56 (1H, m),5.61 (1H, d, J=14.1 Hz), 5.97 (1H, d, J=8.4 Hz), 6.60-7.26 (5H, m), 7.53(1H, d, J=8.4 Hz).

MS: m/z=649.20 [M]⁺.

Example 194

To a pyridine (1.0 mL) solution of compound 98-a (50 mg, 0.10 mmol) wasadded morpholine-4-carbonyl chloride (43 mg, 0.29 mmol), and the mixturewas stirred at 50° C. for 10 hours. Thereafter, to the reaction solutionwere added an aqueous 2N HCl solution and ethyl acetate, the ethylacetate layer was separated, and the aqueous layer was extracted withethyl acetate. To the combined extracts was added sodium sulfide to drythem, then the solvent was distilled off, and the resulting oil waspurified by silica gel column chromatography. The materials were elutedfirstly with chloroform and, then, with chloroform-methanol (97:3, v/v).An objective fraction was concentrated, and washed using diisopropylether to obtain 49 mg of compound of Example 194 as a white solid.

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, 7.1 Hz), 3.60-3.81 (8H, m), 4.30 (1H, d,J=14.3 Hz), 4.44 (1H, d, J=13.3 Hz), 4.89 (1H, d, J=14.8 Hz), 5.19 (1H,s), 5.48-5.62 (2H, m), 5.93 (1H, d, J=7.4 Hz), 6.95-7.24 (7H, m), 7.52(1H, d, J=7.5 Hz).

MS: m/z=635 [M+H]⁺.

Example 195

According to Example 194, compound of Example 195 was synthesized by thesame procedure.

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, 6.5 Hz), 2.97-3.18 (6H, m), 4.29 (1H, d,J=13.73 Hz), 4.44 (1H, d, J=13.3 Hz), 4.89 (1H, d, J=13.5 Hz), 5.21 (1H,brs), 5.47-5.62 (2H, m), 5.94 (1H, brs), 6.97-7.24 (7H, m), 7.51 (1H, d,J=7.9 Hz).

MS: m/z=593 [M+H]⁺.

Example 196, Example 196-b

First Step

Compound 106-a (140 mg, 0.323 mmol) was dissolved in DMF (2 mL), and aDMF (1.0 ml) solution of potassium carbonate (89 mg, 0.646 mmol) anddibenzyl chloromethyl phosphate (158 mg, 0.484 mmol) were added at 0° C.under nitrogen stream. The reaction mixed solution was stirred at roomtemperature for 1 week, and water was added. The mixture was extractedwith ethyl acetate (2×20 mL), and the combined organic layers werewashed with water and an aqueous saturated sodium chloride solution, anddried with sodium sulfate, then filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform-methanol=50:1) to obtain compound of Example 196-b.

¹H-NMR (CDCl₃) δ: 1.01 (6H, dd, J=8.90, 6.88 Hz), 3.58 (1H, d, J=13.09Hz), 4.21 (1H, d, J=13.09 Hz), 4.61-4.73 (2H, m), 5.01-5.10 (5H, m),5.63 (1H, d, J=13.26 Hz), 5.77 (1H, dd, J=13.26, 5.37 Hz), 5.87-5.95(2H, m), 6.81-6.85 (2H, m), 7.02-7.08 (2H, m), 7.13-7.42 (15H, m).

Second Step

Compound 196-b (60 mg, 0.083 mmol) was dissolved in a mixed solvent ofTHF (2 mL) and methanol (2 mL), and 10%-palladium-carbon (10 mg) wasadded. Under hydrogen stream, the mixture was stirred at roomtemperature for 2 hours, and filtered with celite. The filtrate waspurified by preparative HPLC to obtain objective compound of Example196. (18 mg, 40%)

¹H-NMR (DMSO-d₆) δ: 1.01 (6H, dd, J=14.64, 6.86 Hz), 3.90 (1H, d,J=13.27 Hz), 4.32 (1H, d, J=13.57 Hz), 4.59-4.71 (1H, m), 5.01 (1H, d,J=13.42 Hz), 5.43-5.62 (4H, m), 6.17 (1H, d, J=7.63 Hz), 6.80-6.89 (1H,m), 6.91-6.99 (1H, m), 7.07-7.14 (2H, m), 7.27 (1H, t, J=6.63 Hz),7.38-7.52 (4H, m).

Example 197, Example 197-b

First Step

To an acetone (3 ml) solution of (S)-chloromethyl2-(tert-butoxycarbonylamino)-3-methylbutanoate (138 mg, 0.519 mmol) wasadded sodium iodide (390 mg, 2.6 mmol) at room temperature undernitrogen stream, and the mixture was stirred for 20 hours. Afterfiltration, the filtrate was concentrated under reduced pressure, a10%-aqueous sodium thiosulfate solution was added to the residue, andthe mixture was extracted with ethyl acetate (30 mL). The organic layerwas washed with water, dried with sodium sulfate, and filtered, thenconcentrated under reduced pressure. The residue was dissolved inacetone (0.5 mL), compound 106-a (100 mg, 0.231 mmol) and cesiumcarbonate (169 mg, 0.52 mmol) were added to the mixture stirred for 30minutes in acetone (2.5 ml) under nitrogen stream under ice-cooling.This reaction mixture was stirred at room temperature for 4 hours, andconcentrated under reduced pressure, and then water was added. Themixture was extracted with ethyl acetate (2×30 mL), and the combinedorganic layers were washed with water and an aqueous saturated sodiumchloride solution, and dried with sodium sulfate, then filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform-methanol=50:1) to obtain compoundof Example 197-b. (130 mg, 85%)

¹H-NMR (CDCl₃) δ: 0.90-1.11 (12H, m), 1.44 (9H, d, J=9.00 Hz), 2.20-2.41(1H, m), 3.59 (1H, d, J=13.27 Hz), 4.27-4.43 (2H, m), 4.76-4.86 (2H, m),5.10-5.29 (2H, m), 5.68 (1H, dd, J=13.27, 2.44 Hz), 5.81-6.17 (3H, m),6.80-6.94 (2H, m), 7.03-7.15 (2H, m), 7.20-7.44 (5H, m).

MS: m/z=668.05 [M+H]⁺.

Second Step

Compound 197-b (130 mg, 0.196 mmol) was dissolved in ethyl acetate (4ml), a 4N hydrochloric acid ethyl acetate solution (4 ml, 16.00 mmol)was added at room temperature, and the mixture was stirred for 3 hours.After concentration under reduced pressure, the residue was diluted withether, and the solid was filtered to obtain hydrochloride of compound ofExample 197. (85 mg, 72.3%)

¹H-NMR (DMSO-d₆) δ: 0.96-1.05 (11H, m), 2.22-2.28 (1H, m), 3.90 (2H, d,J=12.36 Hz), 4.28 (1H, d, J=13.73 Hz), 4.55-4.65 (1H, m), 4.90-4.99 (1H,m), 5.30 (1H, d, J=7.42 Hz), 5.63 (1H, d, J=13.46 Hz), 5.86-5.89 (4H,m), 6.87-6.96 (2H, m), 7.07-7.16 (2H, m), 7.27-7.32 (2H, m), 7.44-7.49(3H, m), 8.42 (3H, s).

MS: m/z=563.25 [M+H]⁺.

Example 198

According to Example 197, compound of Example 198 was synthesized by thesame procedure.

MS: m/z=651[M+H]⁺.

Example 199

A DMF (1 ml) solution of compound 106-a (33 mg, 0.076 mmol) andtriethylamine (24 mg, 0.235 mmol) was cooled to 1 to 3° C., andchloromethyl methyl ether (12.6 mg, 0.157 mmol) was added dropwise whilethe same temperature was retained. After the reaction solution wasstirred at the same temperature for 30 minutes, water was added, and themixture was extracted with ethyl acetate three times. The extract waswashed with water three times, and dried with sodium sulfate, then thesolvent was distilled off. The resulting solid was washed withethyl-diisopropyl ether to obtain 22 mg of compound of Example 199.

¹H-NMR (CDCl₃) δ: 1.08 (3H, d, J=7.2 Hz), 1.11 (3H, d, J=7.2 Hz), 3.59(1H, d, J=13.2 Hz), 3.64 (3H, s), 4.32 (1H, d, J=12.9 Hz), 4.77-4.85(2H, m), 5.14 (1H, s), 5.32 (1H, d, J=6.0 Hz), 5.50 (1H, d, J=6.0 Hz),5.70 (1H, d, J=13.2 Hz), 5.90 (1H, d, J=6.9 Hz), 6.77-6.84 (2H, m),7.05-7.07 (2H, m), 7.18-7.28 (3H, m), 7.33-7.43 (2H, m).

Example 200

A DMF (1 ml) solution of 4-(hydroxymethyl)phenyl acetate (53 mg, 0.287mmol) and sodium iodide (72 mg, 0.48 mmol) was stirred at roomtemperature for 30 minutes. To the reaction solution were addedpotassium carbonate (66 mg, 0.48 mmol) and compound 98-a (50 mg, 0.0958mmol), and the mixture was further stirred at the same temperature for 5hours. The reaction solution was diluted with ethyl acetate (10 ml), andwater was added. The organic layer was separated, and the aqueous layerwas extracted with ethyl acetate once. The extract was washed with waterthree times, and dried with sodium sulfate, and the solvent wasdistilled off. The resulting crude product was purified by silica gelcolumn chromatography. The materials were eluted firstly with ethylacetate and, then, with ethyl acetate-methanol (7:3, v/v). Concentrationof an objective fraction afforded 34 mg of compound of Example 200 as asolid.

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, J=7.2 Hz), 2.28 (3H, s), 4.29 (1H, d,J=13.8 Hz), 4.38 (1H, d, J=13.2 Hz), 4.81 (1H, d, J=12.9 Hz), 5.08 (1H,s), 5.45 (1H, d, J=10.8 Hz), 5.52-5.61 (2H, m), 5.87 (1H, d, J=7.5 Hz),6.57 (1H, d, J=7.5 Hz), 6.73-6.79 (1H, m), 7.04-7.20 (7H, m), 7.51 (1H,d, J=7.2 Hz), 7.57 (2H, d, J=8.4 Hz).

Example 201

First Step

Compound 106-a (80.0 mg, 0.185 mmol) synthesized according to Exampleand 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (41.1 mg, 0.277 mmol)were dissolved in DMF (1 ml), potassium carbonate (93.0 mg, 0.673 mmol)was added, and the mixture was stirred at 50° C. for 2 hours. To thereaction solution was added water, the mixture was extracted with ethylacetate, and the organic layer was washed with water, and dried withsodium sulfate. The solvent was distilled off under reduced pressure,and the resulting crude product was purified by silica gel columnchromatography, and eluted with chloroform-methanol (95:5, v/v).Dichloromethane-diethyl ether were added, and the mixture was solidifiedto obtain 60 mg of compound of Example 201 as a white solid.

¹H-NMR (DMSO-d₆) δ: 1.00 (6H, s), 2.10 (3H, s), 3.89 (1H, d, J=13.1 Hz),4.25 (1H, d, J=12.7 Hz), 4.59 (1H, m), 4.90-5.04 (3H, m), 5.27 (1H, s),5.62 (1H, d, J=13.3 Hz), 5.83 (1H, d, J=4.9 Hz), 6.91-7.44 (9H, m).

MS: m/z=546 [M+H]⁺.

Example 202

¹H-NMR (CDCl₃) δ: 1.18 (3H, d, J=7.2 Hz), 2.18 (3H, s), 4.33 (1H, d,J=13.8 Hz), 4.43 (1H, d, J=13.2 Hz), 4.86 (1H, d, J=13.5 Hz), 5.15 (1H,d, J=13.5 Hz), 5.17 (1H, s), 5.35 (1H, d, J=13.8 Hz), 5.48-5.59 (2H, m),5.94 (1H, d, J=13.8 Hz), 6.77 (1H, d, J=7.5 Hz), 6.86-6.91 (1H, m),7.07-7.26 (5H, m), 7.50-7.53 (1H, m).

Example 203

A DMF (1.0 mL) solution of compound 98-a (50 mg, 0.10 mmol) wasice-cooled, and triethylamine (0.040 ml, 0.29 mmol) and1-(chloromethoxy)-2-methoxyethane (24 mg, 0.19 mmol) were added, and themixture was stirred for 1 hour under ice-cooling, then stirred at roomtemperature overnight. Thereafter, to the reaction solution were addedwater and ethyl acetate, the ethyl acetate layer was separated, and theaqueous layer was extracted with ethyl acetate. The combined extractswere washed with water and brine, and then sodium sulfide was added todry them. The solvent was distilled off, and the resulting oil waspurified by silica gel column chromatography. The materials were elutedfirstly with chloroform and, then, with chloroform-methanol (97:3, v/v).An objective fraction was concentrated, and washed using diisopropylether to obtain 18 mg of compound of Example 203 as a white solid.

¹H-NMR (CDCl₃) δ: 1.19 (3H, d, 7.6 Hz), 3.36 (3H, s), 3.51-3.55 (2H, m),3.93-4.00 (2H, m), 4.32 (1H, d, 14.2 Hz), 4.43 (1H, d, J=13.3 Hz), 4.88(1H, d, J=12.8 Hz), 5.14 (1H, s), 5.55-5.66 (3H, m), 5.90 (1H, d, J=7.8Hz), 6.73-6.85 (2H, m), 7.09-7.22 (5H, m), 7.53 (1H, d, J=8.9 Hz).

MS: m/z=610 [M+H]⁺.

Example 204

¹H-NMR (CDCl₃) δ: 1.06 (3H, d, J=7.1 Hz), 1.09 (3H, d, J=7.1 Hz), 2.43(3H, s), 3.59 (1H, d, J=13.5 Hz), 4.34 (1H, d, J=13.2 Hz), 4.70-4.86(2H, m), 5.14 (1H, s), 5.70 (1H, d, J=13.5 Hz), 5.94 (1H, d, J=7.7 Hz),6.81-6.92 (2H, m), 7.03-7.08 (2H, m), 7.15-7.26 (3H, m), 7.32-7.44 (2H,m).

MS: m/z=476 [M+H]⁺.

Example 205

¹H-NMR (CDCl₃) δ: 1.02-1.15 (9H, m), 1.39 (3H, d, J=6.9 Hz), 1.58-1.72(1H, m), 1.90-2.05 (1H, m), 2.71-2.84 (1H, m), 3.59 (1H, d, J=13.2 Hz),4.34 (1H, d, J=12.9 Hz), 4.69-4.90 (2H, m), 5.15 (1H, s), 5.70 (1H, d,J=12.9 Hz), 5.86-5.98 (1H, m), 6.76-6.99 (2H, m), 7.04-7.10 (2H, m),7.15-7.29 (3H, m), 7.32-7.44 (2H, m).

MS: m/z=518 [M+H]⁺.

Example 206

¹H-NMR (CDCl₃) δ: 2.41 (3H, s), 3.58 (1H, d, J=13.5 Hz), 4.41-4.87 (6H,m), 5.07 (1H, d, J=13.2 Hz), 5.26 (1H, s), 5.65 (1H, d, J=13.5 Hz), 5.97(1H, d, J=7.7 Hz), 6.80-6.92 (2H, m), 7.04-7.10 (2H, m), 7.25-7.45 (5H,m).

MS: m/z=512 [M+H]⁺.

Example 207

¹H-NMR (CDCl₃) δ: 1.20 (3H, d, J=7.3 Hz), 2.44 (3H, s), 4.32 (1H, d,J=13.9 Hz), 4.46 (1H, d, J=13.3 Hz), 4.93 (1H, d, J=13.3 Hz), 5.16 (1H,s), 5.45-5.58 (1H, m), 5.61 (1H, d, J=13.9 Hz), 5.97 (1H, d, J=7.9 Hz),6.80-6.94 (2H, m), 7.05-7.13 (3H, m), 7.15-7.24 (2H, m), 7.53 (1H, d,J=7.8 Hz).

MS: m/z=564 [M+H]⁺.

Example 208

¹H-NMR (CDCl₃) δ: 1.13 (3H, d, J=7.3 Hz), 3.63 (1H, d, J=13.4 Hz), 4.48(1H, d, J=13.1 Hz), 4.95 (1H, d, J=13.0 Hz), 5.17 (1H, s), 5.44-5.58(1H, m), 5.65 (1H, d, J=13.0 Hz), 6.02 (1H, d, J=7.9 Hz), 6.90-7.61(12H, m).

MS: m/z=628 [M+H]⁺.

Example 209

¹H-NMR (CDCl₃) δ: 1.16 (3H, d, J=7.4 Hz), 1.99-2.15 (4H, m), 2.93-3.06(1H, m), 3.47-3.58 (2H, m), 4.01-4.16 (3H, m), 4.45 (1H, d, J=13.2 Hz),4.93 (1H, d, J=13.5 Hz), 5.18 (1H, s), 5.35 (1H, d, J=14.0 Hz),5.43-5.56 (1H, m), 5.95 (1H, d, J=7.7 Hz), 6.82-7.02 (3H, m), 7.06-7.15(2H, m), 7.19-7.26 (3H, m).

MS: m/z=618 [M+H]⁺.

Example 210

Step

To compound 210-a (101 mg, 0.193 mmol) were added dimethylformamide (1mL), HATU (50 mg, 0.148 mmol) and N-methylmorpholine (0.041 mL, 0.370mmol), and the mixture was stirred at room temperature for 6 hours. Thereaction solution was purified by preparative LCMS (method 14) to obtaincompound of Example 210 (50 mg, yield 51%).

¹H-NMR (DMSO-d₆) δ: 7.53 (s, 1H), 7.47 (s, 3H), 7.20 (s, 2H), 6.99 (s,1H), 6.87 (s, 1H), 6.17 (s, 1H), 5.83 (s, 1H), 5.61 (d, J=13.0 Hz, 1H),5.50 (s, 1H), 5.24 (d, J=13.0 Hz, 1H), 4.67 (d, J=13.0 Hz, 1H), 4.04 (d,J=11.0 Hz, 1H), 3.10 (s, 6H), 3.05 (s, 6H), 1.09 (s, 3H).

MS: m/z=620 [M+H]⁺. RT=1.73 min.

Example 211

MS: m/z=645 [M+H]⁺. RT=2.53 min.

Example 212

MS: m/z=662 [M+H]⁺. RT=2.35 min.

Example 213

MS: m/z=590 [M+H]⁺. RT=2.17 min.

Example 214

MS: m/z=712 [M+H]⁺. RT=2.52 min.

Example 215

MS: m/z=618 [M+H]⁺. RT=2.56 min.

Example 216

MS: m/z=654 [M+H]⁺. RT=2.71 min.

Example 217

MS: m/z=645 [M+H]⁺. RT=2.35 min.

Example 218

MS: m/z=590 [M+H]⁺. RT=2.19 min.

Example 219

MS: m/z=608 [M+H]⁺. RT=2.17 min.

Example 220

MS: m/z=578 [M+H]⁺. RT=2.23 min.

Example 221

MS: m/z=648 [M+H]⁺. RT=2.24 min.

Example 222

MS: m/z=592 [M+H]⁺. RT=2.38 min.

Example 223

MS: m/z=606 [M+H]⁺. RT=2.10 min.

Example 224

MS: m/z=592 [M+H]⁺. RT=2.38 min.

Example 225

MS: m/z=526 [M+H]⁺. RT=2.27 min.

Example 226

MS: m/z=626 [M+H]⁺. RT=2.38 min.

Example 227

MS: m/z=632 [M+H]⁺. RT=2.69 min.

Example 228

MS: m/z=576.11 [M+H]⁺

Example 229

MS: m/z=643.88 [M+H]⁺.

Example 230

MS: m/z=636.88 [M+H] P.

Example 231

MS: m/z=681.26 [M+H]⁺.

Example 232

MS: m/z=735.19 [M+H]⁺.

Example 233

MS: m/z=721.22 [M+H]⁺.

Example 234

MS: m/z=731.19 [M+H]⁺

Example 235

¹H-NMR (CDCl₃) δ: 1.09 (d, J=7.2 Hz, 3H), 3.65 (d, J=13.8 Hz, 1H), 3.82(s, 3H), 4.39 (d, J=13.2 Hz, 1H), 4.87 (d, J=13.2 Hz, 1H), 5.52 (m, 1H),5.63 (d, J=13.8 Hz, 1H), 5.88 (d, J=6.6 Hz, 1H), 5.94 (s, 1H), 6.00 (d,J=6.6 Hz, 1H), 6.88-6.98 (m, 2H), 7.14-7.19 (m, 2H), 7.27-7.38 (m, 3H),7.52 (s, 1H).

MS: m/z=644.2 [M+H]⁺.

Example 236

MS: m/z=654 [M+H]⁺.

Example 237

MS: m/z=654 [M+H]⁺.

Example 238

MS: m/z=564.15 [M+H]⁺.

Example 239

¹H-NMR (CDCl₃) δ: 1.09 (d, J=7.1 Hz, 3H), 3.55 (s, 3H), 3.63 (d, J=13.5Hz, 1H), 4.40 (d, J=13.2 Hz, 1H), 4.87 (d, J=13.2 Hz, 1H), 5.26 (d,J=6.0 Hz, 1H), 5.51-5.70 (m, 3H), 5.89-5.95 (m, 2H), 6.84-6.89 (m, 2H),7.07-7.20 (m, 3H), 7.26-7.37 (m, 3H).

Example 240

¹H-NMR (CDCl₃) δ: 1.10 (d, J=7.1 Hz, 3H), 2.48 (s, 3H), 3.63 (d, J=13.5Hz, 1H), 3.83 (s, 3H), 4.41 (d, J=13.2 Hz, 1H), 4.87 (d, J=13.2 Hz, 1H),5.47-5.58 (m, 1H), 5.68 (d, J=13.5 Hz, 1H), 5.87 (d, J=6.6 Hz, 1H), 5.93(s, 1H), 6.01 (d, J=6.6 Hz, 1H), 6.84-6.91 (m, 1H), 6.95 (d, J=7.4 Hz,1H), 7.05-7.15 (m, 2H), 7.25-7.38 (m, 3H), 7.93 (s, 1H).

Example 241

¹H-NMR (CDCl₃) δ: 1.21 (d, J=7.1 Hz, 3H), 3.83 (s, 3H), 4.11 (d, J=13.7Hz, 1H), 4.42 (d, J=13.2 Hz, 1H), 4.91 (d, J=13.2 Hz, 1H), 5.13 (s, 1H),5.40 (dd, J=13.7, 2.6 Hz, 1H), 5.49-5.59 (m, 1H), 5.87 (d, J=6.6 Hz,1H), 5.93-5.96 (m, 2H), 6.79 (d, J=7.4 Hz, 1H), 6.84-6.91 (m, 1H), 6.97(dd, J=8.7, 4.3 Hz, 1H), 7.04-7.15 (m, 3H), 7.26 (d, J=4.7 Hz, 1H).

LCMS measurement conditions of compounds of Reference examples andExamples are described below.

1) Conditions for the case where not specifically stated;

Column: ACQUITY UPLC(R)BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters)

Flow rate: 0.8 mL/min.UV detection wavelength: 254 nmMobile phase: an aqueous solution containing 0.1% formic acid for [A],an acetonitrile solution containing 0.1% formic acid for [B]Gradient: a linear gradient of 10% to 100% solvent [B] was performedover 3.5 minutes, and 100% solvent [B] was retained for 0.5 minutes.

2) Method 6; Column: Gemini-NX (5 μm, i.d. 4.6×50 mm) (Phenomenex)

Flow rate: 3 mL/min.UV detection wavelength: 254 nmMobile phase: an aqueous solution containing 0.1% formic acid for [A],an acetonitrile solution containing 0.1% formic acid for [B]Gradient: a linear gradient of 5% to 100% solvent [B] was performed over3.5 minutes, and 100% solvent [B] was retained for 0.5 minutes.

3) Method 14; Column: Gemini-NX (C18, 5 μm, AXIA Packed, i.d. 21.2×50mm) (Phenomenex)

Flow rate: 25 mL/min.UV detection wavelength: 254 nmMobile phase: an aqueous solution containing 0.1% formic acid for [A],an acetonitrile solution containing 0.1% formic acid for [B]

Gradient:

Narrow Gradient (6 min): a linear gradient of X % to Y % solvent [B] wasperformed over 4 minutes, and 100% solvent [B] was retained for 1minute.

Intermediate compound i-7: X=35, Y=55

Intermediate compound i-10: X=30, Y=50

Intermediate compound i-14: X=30, Y=50

Example 210: X=20, Y=40

Standard Gradient (7 min): a linear gradient of 10% to 100% solvent [B]was performed over 5 minutes, and 100% solvent [B] was retained for 1minute.

Further, the following combinations of substituents can be alsosynthesized by the method described in the above Reference examples andExamples, and are a preferable embodiment of the present invention.

Compounds in which, in the following formula (I):

combinations of R^(3a) and R^(7a) of the following formulae (I-A) and(I-B):

(wherein P^(R) is same as that of item 1)

are selected from the following Tables 15 to 20, respectively.

Combinations of (R^(3a),R^(7a))(R3-1, R7-1), (R3-1, R7-2), (R3-1, R7-3), (R3-1, R7-4), (R3-1, R7-5),(R3-1, R7-6), (R3-1, R7-7), (R3-1, R7-8), (R3-1, R7-9), (R3-1, R7-10),(R3-1, R7-1l), (R3-1, R7-12), (R3-1, R7-13), (R3-1, R7-14), (R3-1,R7-15), (R3-1, R7-16), (R3-1, R7-17), (R3-1, R7-18), (R3-1, R7-19),(R3-1, R7-20), (R3-1, R7-21), (R3-1, R7-22), (R3-1, R7-23), (R3-1,R7-24), (R3-1, R7-25), (R3-1, R7-26), (R3-1, R7-27), (R3-1, R7-28),(R3-1, R7-29), (R3-1, R7-30), (R3-1, R7-31), (R3-1, R7-32), (R3-1,R7-33), (R3-1, R7-34), (R3-1, R7-35), (R3-1, R7-36), (R3-1, R7-37),(R3-1, R7-38), (R3-1, R7-39), (R3-1, R7-40), (R3-1, R7-41), (R3-1,R7-42), (R3-1, R7-43), (R3-1, R7-44), (R3-1, R7-45), (R3-1, R7-46),(R3-1, R7-47), (R3-1, R7-48), (R3-1, R7-49), (R3-1, R7-50), (R3-1,R7-51), (R3-1, R7-52), (R3-1, R7-53), (R3-1, R7-54), (R3-1, R7-55),(R3-1, R7-56), (R3-1, R7-57), (R3-1, R7-58), (R3-1, R7-59), (R3-1,R7-60), (R3-1, R7-61), (R3-1, R7-62), (R3-1, R7-63), (R3-1, R7-64),(R3-1, R7-65), (R3-1, R7-66), (R3-1, R7-67), (R3-1, R7-68), (R3-1,R7-69), (R3-1, R7-70), (R3-1, R7-71), (R3-1, R7-72), (R3-1, R7-73),(R3-1, R7-74), (R3-1, R7-75), (R3-1, R7-76), (R3-1, R7-77),(R3-2, R7-1), (R3-2, R7-2), (R3-2, R7-3), (R3-2, R7-4), (R3-2, R7-5),(R3-2, R7-6), (R3-2, R7-7), (R3-2, R7-8), (R3-2, R7-9), (R3-2, R7-10),(R3-2, R7-11), (R3-2, R7-12), (R3-2, R7-13), (R3-2, R7-14), (R3-2,R7-15), (R3-2, R7-16), (R3-2, R7-17), (R3-2, R7-18), (R3-2, R7-19),(R3-2, R7-20), (R3-2, R7-21), (R3-2, R7-22), (R3-2, R7-23), (R3-2,R7-24), (R3-2, R7-25), (R3-2, R7-26), (R3-2, R7-27), (R3-2, R7-28),(R3-2, R7-29), (R3-2, R7-30), (R3-2, R7-31), (R3-2, R7-32), (R3-2,R7-33), (R3-2, R7-34), (R3-2, R7-35), (R3-2, R7-36), (R3-2, R7-37),(R3-2, R7-38), (R3-2, R7-39), (R3-2, R7-40), (R3-2, R7-41), (R3-2,R7-42), (R3-2, R7-43), (R3-2, R7-44), (R3-2, R7-45), (R3-2, R7-46),(R3-2, R7-47), (R3-2, R7-48), (R3-2, R7-49), (R3-2, R7-50), (R3-2,R7-51), (R3-2, R7-52), (R3-2, R7-53), (R3-2, R7-54), (R3-2, R7-55),(R3-2, R7-56), (R3-2, R7-57), (R3-2, R7-58), (R3-2, R7-59), (R3-2,R7-60), (R3-2, R7-61), (R3-2, R7-62), (R3-2, R7-63), (R3-2, R7-64),(R3-2, R7-65), (R3-2, R7-66), (R3-2, R7-67), (R3-2, R7-68), (R3-2,R7-69), (R3-2, R7-70), (R3-2, R7-71), (R3-2, R7-72), (R3-2, R7-73),(R3-2, R7-74), (R3-2, R7-75), (R3-2, R7-76), (R3-2, R7-77),(R3-3, R7-1), (R3-3, R7-2), (R3-3, R7-3), (R3-3, R7-4), (R3-3, R7-5),(R3-3, R7-6), (R3-3, R7-7), (R3-3, R7-8), (R3-3, R7-9), (R3-3, R7-10),(R3-3, R7-11), (R3-3, R7-12), (R3-3, R7-13), (R3-3, R7-14), (R3-3,R7-15), (R3-3, R7-16), (R3-3, R7-17), (R3-3, R7-18), (R3-3, R7-19),(R3-3, R7-20), (R3-3, R7-21), (R3-3, R7-22), (R3-3, R7-23), (R3-3,R7-24), (R3-3, R7-25), (R3-3, R7-26), (R3-3, R7-27), (R3-3, R7-28),(R3-3, R7-29), (R3-3, R7-30), (R3-3, R7-31), (R3-3, R7-32), (R3-3,R7-33), (R3-3, R7-34), (R3-3, R7-35), (R3-3, R7-36), (R3-3, R7-37),(R3-3, R7-38), (R3-3, R7-39), (R3-3, R7-40), (R3-3, R7-41), (R3-3,R7-42), (R3-3, R7-43), (R3-3, R7-44), (R3-3, R7-45), (R3-3, R7-46),(R3-3, R7-47), (R3-3, R7-48), (R3-3, R7-49), (R3-3, R7-50), (R3-3,R7-51), (R3-3, R7-52), (R3-3, R7-53), (R3-3, R7-54), (R3-3, R7-55),(R3-3, R7-56), (R3-3, R7-57), (R3-3, R7-58), (R3-3, R7-59), (R3-3,R7-60), (R3-3, R7-61), (R3-3, R7-62), (R3-3, R7-63), (R3-3, R7-64),(R3-3, R7-65), (R3-3, R7-66), (R3-3, R7-67), (R3-3, R7-68), (R3-3,R7-69), (R3-3, R7-70), (R3-3, R7-71), (R3-3, R7-72), (R3-3, R7-73),(R3-3, R7-74), (R3-3, R7-75), (R3-3, R7-76), (R3-3, R7-77).

TABLE 15 R^(3a)   R3-1

R3-2

R3-3

TABLE 16 R^(7a)   R7-1 

R7-2 

R7-3 

R7-4 

R7-5 

R7-6 

R7-7 

R7-8 

R7-9 

R7-10

R7-11

R7-12

R7-13

R7-14

R7-15

R7-16

R7-17

R7-18

TABLE 17 R^(7a)   R7-19

R7-20

R7-21

R7-22

R7-23

R7-24

R7-25

R7-26

R7-27

R7-28

R7-29

R7-30

R7-31

R7-32

R7-33

R7-34

R7-35

R7-36

TABLE 18 R^(7a)   R7-37

R7-38

R7-39

R7-40

R7-41

R7-42

R7-43

R7-44

R7-45

R7-46

R7-47

R7-48

R7-49

R7-50

R7-51

R7-52

R7-53

R7-54

TABLE 19 R^(7a)   R7-55

R7-56

R7-57

R7-58

R7-59

R7-60

R7-61

R7-62

R7-63

R7-64

R7-65

R7-66

R7-67

R7-68

R7-69

R7-70

R7-71

R7-72

TABLE 20 R^(7a)   R7-73

R7-74

R7-75

R7-76

R7-77

In addition, the following combinations of substituents can be alsosynthesized by the method described in the above Reference examples andExamples, and are a preferable embodiment of the present invention.

Compounds in which,

combinations of P^(R) and R^(7a) of the following formula (I-C):

are selected from the following Table 21 and the above Tables 15 to 20,respectively.

Combinations of (P^(R),R^(7a))(PR-1, R7-1), (PR-1, R7-2), (PR-1, R7-3), (PR-1, R7-4), (PR-1, R7-5),(PR-1, R7-6), (PR-1, R7-7), (PR-1, R7-8), (PR-1, R7-9), (PR-1, R7-10),(PR-1, R7-11), (PR-1, R7-12), (PR-1, R7-13), (PR-1, R7-14), (PR-1,R7-15), (PR-1, R7-16), (PR-1, R7-17), (PR-1, R7-18), (PR-1, R7-19),(PR-1, R7-20), (PR-1, R7-21), (PR-1, R7-22), (PR-1, R7-23), (PR-1,R7-24), (PR-1, R7-25), (PR-1, R7-26), (PR-1, R7-27), (PR-1, R7-28),(PR-1, R7-29), (PR-1, R7-30), (PR-1, R7-31), (PR-1, R7-32), (PR-1,R7-33), (PR-1, R7-34), (PR-1, R7-35), (PR-1, R7-36), (PR-1, R7-37),(PR-1, R7-38), (PR-1, R7-39), (PR-1, R7-40), (PR-1, R7-41), (PR-1,R7-42), (PR-1, R7-43), (PR-1, R7-44), (PR-1, R7-45), (PR-1, R7-46),(PR-1, R7-47), (PR-1, R7-48), (PR-1, R7-49), (PR-1, R7-50), (PR-1,R7-51), (PR-1, R7-52), (PR-1, R7-53), (PR-1, R7-54), (PR-1, R7-55),(PR-1, R7-56), (PR-1, R7-57), (PR-1, R7-58), (PR-1, R7-59), (PR-1,R7-60), (PR-1, R7-61), (PR-1, R7-62), (PR-1, R7-63), (PR-1, R7-64),(PR-1, R7-65), (PR-1, R7-66), (PR-1, R7-67), (PR-1, R7-68), (PR-1,R7-69), (PR-1, R7-70), (PR-1, R7-71), (PR-1, R7-72), (PR-1, R7-73),(PR-1, R7-74), (PR-1, R7-75), (PR-1, R7-76), (PR-1, R7-77),(PR-2, R7-1), (PR-2, R7-2), (PR-2, R7-3), (PR-2, R7-4), (PR-2, R7-5),(PR-2, R7-6), (PR-2, R7-7), (PR-2, R7-8), (PR-2, R7-9), (PR-2, R7-10),(PR-2, R7-11), (PR-2, R7-12), (PR-2, R7-13), (PR-2, R7-14), (PR-2,R7-15), (PR-2, R7-16), (PR-2, R7-17), (PR-2, R7-18), (PR-2, R7-19),(PR-2, R7-20), (PR-2, R7-21), (PR-2, R7-22), (PR-2, R7-23), (PR-2,R7-24), (PR-2, R7-25), (PR-2, R7-26), (PR-2, R7-27), (PR-2, R7-28),(PR-2, R7-29), (PR-2, R7-30), (PR-2, R7-31), (PR-2, R7-32), (PR-2,R7-33), (PR-2, R7-34), (PR-2, R7-35), (PR-2, R7-36), (PR-2, R7-37),(PR-2, R7-38), (PR-2, R7-39), (PR-2, R7-40), (PR-2, R7-41), (PR-2,R7-42), (PR-2, R7-43), (PR-2, R7-44), (PR-2, R7-45), (PR-2, R7-46),(PR-2, R7-47), (PR-2, R7-48), (PR-2, R7-49), (PR-2, R7-50), (PR-2,R7-51), (PR-2, R7-52), (PR-2, R7-53), (PR-2, R7-54), (PR-2, R7-55),(PR-2, R7-56), (PR-2, R7-57), (PR-2, R7-58), (PR-2, R7-59), (PR-2,R7-60), (PR-2, R7-61), (PR-2, R7-62), (PR-2, R7-63), (PR-2, R7-64),(PR-2, R7-65), (PR-2, R7-66), (PR-2, R7-67), (PR-2, R7-68), (PR-2,R7-69), (PR-2, R7-70), (PR-2, R7-71), (PR-2, R7-72), (PR-2, R7-73),(PR-2, R7-74), (PR-2, R7-75), (PR-2, R7-76), (PR-2, R7-77),(PR-3, R7-1), (PR-3, R7-2), (PR-3, R7-3), (PR-3, R7-4), (PR-3, R7-5),(PR-3, R7-6), (PR-3, R7-7), (PR-3, R7-8), (PR-3, R7-9), (PR-3, R7-10),(PR-3, R7-11), (PR-3, R7-12), (PR-3, R7-13), (PR-3, R7-14), (PR-3,R7-15), (PR-3, R7-16), (PR-3, R7-17), (PR-3, R7-18), (PR-3, R7-19),(PR-3, R7-20), (PR-3, R7-21), (PR-3, R7-22), (PR-3, R7-23), (PR-3,R7-24), (PR-3, R7-25), (PR-3, R7-26), (PR-3, R7-27), (PR-3, R7-28),(PR-3, R7-29), (PR-3, R7-30), (PR-3, R7-31), (PR-3, R7-32), (PR-3,R7-33), (PR-3, R7-34), (PR-3, R7-35), (PR-3, R7-36), (PR-3, R7-37),(PR-3, R7-38), (PR-3, R7-39), (PR-3, R7-40), (PR-3, R7-41), (PR-3,R7-42), (PR-3, R7-43), (PR-3, R7-44), (PR-3, R7-45), (PR-3, R7-46),(PR-3, R7-47), (PR-3, R7-48), (PR-3, R7-49), (PR-3, R7-50), (PR-3,R7-51), (PR-3, R7-52), (PR-3, R7-53), (PR-3, R7-54), (PR-3, R7-55),(PR-3, R7-56), (PR-3, R7-57), (PR-3, R7-58), (PR-3, R7-59), (PR-3,R7-60), (PR-3, R7-61), (PR-3, R7-62), (PR-3, R7-63), (PR-3, R7-64),(PR-3, R7-65), (PR-3, R7-66), (PR-3, R7-67), (PR-3, R7-68), (PR-3,R7-69), (PR-3, R7-70), (PR-3, R7-71), (PR-3, R7-72), (PR-3, R7-73),(PR-3, R7-74), (PR-3, R7-75), (PR-3, R7-76), (PR-3, R7-77),(PR-4, R7-1), (PR-4, R7-2), (PR-4, R7-3), (PR-4, R7-4), (PR-4, R7-5),(PR-4, R7-6), (PR-4, R7-7), (PR-4, R7-8), (PR-4, R7-9), (PR-4, R7-10),(PR-4, R7-11), (PR-4, R7-12), (PR-4, R7-13), (PR-4, R7-14), (PR-4,R7-15), (PR-4, R7-16), (PR-4, R7-17), (PR-4, R7-18), (PR-4, R7-19),(PR-4, R7-20), (PR-4, R7-21), (PR-4, R7-22), (PR-4, R7-23), (PR-4,R7-24), (PR-4, R7-25), (PR-4, R7-26), (PR-4, R7-27), (PR-4, R7-28),(PR-4, R7-29), (PR-4, R7-30), (PR-4, R7-31), (PR-4, R7-32), (PR-4,R7-33), (PR-4, R7-34), (PR-4, R7-35), (PR-4, R7-36), (PR-4, R7-37),(PR-4, R7-38), (PR-4, R7-39), (PR-4, R7-40), (PR-4, R7-41), (PR-4,R7-42), (PR-4, R7-43), (PR-4, R7-44), (PR-4, R7-45), (PR-4, R7-46),(PR-4, R7-47), (PR-4, R7-48), (PR-4, R7-49), (PR-4, R7-50), (PR-4,R7-51), (PR-4, R7-52), (PR-4, R7-53), (PR-4, R7-54), (PR-4, R7-55),(PR-4, R7-56), (PR-4, R7-57), (PR-4, R7-58), (PR-4, R7-59), (PR-4,R7-60), (PR-4, R7-61), (PR-4, R7-62), (PR-4, R7-63), (PR-4, R7-64),(PR-4, R7-65), (PR-4, R7-66), (PR-4, R7-67), (PR-4, R7-68), (PR-4,R7-69), (PR-4, R7-70), (PR-4, R7-71), (PR-4, R7-72), (PR-4, R7-73),(PR-4, R7-74), (PR-4, R7-75), (PR-4, R7-76), (PR-4, R7-77),(PR-5, R7-1), (PR-5, R7-2), (PR-5, R7-3), (PR-5, R7-4), (PR-5, R7-5),(PR-5, R7-6), (PR-5, R7-7), (PR-5, R7-8), (PR-5, R7-9), (PR-5, R7-10),(PR-5, R7-11), (PR-5, R7-12), (PR-5, R7-13), (PR-5, R7-14), (PR-5,R7-15), (PR-5, R7-16), (PR-5, R7-17), (PR-5, R7-18), (PR-5, R7-19),(PR-5, R7-20), (PR-5, R7-21), (PR-5, R7-22), (PR-5, R7-23), (PR-5,R7-24), (PR-5, R7-25), (PR-5, R7-26), (PR-5, R7-27), (PR-5, R7-28),(PR-5, R7-29), (PR-5, R7-30), (PR-5, R7-31), (PR-5, R7-32), (PR-5,R7-33), (PR-5, R7-34), (PR-5, R7-35), (PR-5, R7-36), (PR-5, R7-37),(PR-5, R7-38), (PR-5, R7-39), (PR-5, R7-40), (PR-5, R7-41), (PR-5,R7-42), (PR-5, R7-43), (PR-5, R7-44), (PR-5, R7-45), (PR-5, R7-46),(PR-5, R7-47), (PR-5, R7-48), (PR-5, R7-49), (PR-5, R7-50), (PR-5,R7-51), (PR-5, R7-52), (PR-5, R7-53), (PR-5, R7-54), (PR-5, R7-55),(PR-5, R7-56), (PR-5, R7-57), (PR-5, R7-58), (PR-5, R7-59), (PR-5,R7-60), (PR-5, R7-61), (PR-5, R7-62), (PR-5, R7-63), (PR-5, R7-64),(PR-5, R7-65), (PR-5, R7-66), (PR-5, R7-67), (PR-5, R7-68), (PR-5,R7-69), (PR-5, R7-70), (PR-5, R7-71), (PR-5, R7-72), (PR-5, R7-73),(PR-5, R7-74), (PR-5, R7-75), (PR-5, R7-76), (PR-5, R7-77).

TABLE 21

  PR-1

PR-2

PR-3

PR-4

PR-5

Further, in the above compounds of Reference examples 1 to 775, thefollowing combinations in which a part corresponding to —OH group of thefollowing formula (II):

(wherein each substituent is same meaning as that of item 1)

are converted into a prodrug by PR-1 to PR-5 in the above Table 21 arealso a preferable embodiment of the present invention. These compoundscan be also synthesized by a general method known to a person skilled inthe art or the method described in Examples, using the above compound ofReference example as a raw material.

Combinations of (Number of compound of Reference example, P^(R))(Reference example 1, PR-1), (Reference example 1, PR-2), (Referenceexample 1, PR-3), (Reference example 1, PR-4), (Reference example 1,PR-5), (Reference example 2, PR-1), (Reference example 2, PR-2),(Reference example 2, PR-3), (Reference example 2, PR-4), (Referenceexample 2, PR-5), (Reference example 3, PR-1), (Reference example 3,PR-2), (Reference example 3, PR-3), (Reference example 3, PR-4),(Reference example 3, PR-5), (Reference example 4, PR-1), (Referenceexample 4, PR-2), (Reference example 4, PR-3), (Reference example 4,PR-4), (Reference example 4, PR-5), (Reference example 5, PR-1),(Reference example 5, PR-2), (Reference example 5, PR-3), (Referenceexample 5, PR-4), (Reference example 5, PR-5), (Reference example 6,PR-1), (Reference example 6, PR-2), (Reference example 6, PR-3),(Reference example 6, PR-4), (Reference example 6, PR-5), (Referenceexample 7, PR-1), (Reference example 7, PR-2), (Reference example 7,PR-3), (Reference example 7, PR-4), (Reference example 7, PR-5),(Reference example 8, PR-1), (Reference example 8, PR-2), (Referenceexample 8, PR-3), (Reference example 8, PR-4), (Reference example 8,PR-5), (Reference example 9, PR-1), (Reference example 9, PR-2),(Reference example 9, PR-3), (Reference example 9, PR-4), (Referenceexample 9, PR-5), (Reference example 10, PR-1), (Reference example 10,PR-2), (Reference example 10, PR-3), (Reference example 10, PR-4),(Reference example 10, PR-5), (Reference example 11, PR-1), (Referenceexample 11, PR-2), (Reference example 11, PR-3), (Reference example 11,PR-4), (Reference example 11, PR-5), (Reference example 12, PR-1),(Reference example 12, PR-2), (Reference example 12, PR-3), (Referenceexample 12, PR-4), (Reference example 12, PR-5), (Reference example 13,PR-1), (Reference example 13, PR-2), (Reference example 13, PR-3),(Reference example 13, PR-4), (Reference example 13, PR-5), (Referenceexample 14, PR-1), (Reference example 14, PR-2), (Reference example 14,PR-3), (Reference example 14, PR-4), (Reference example 14, PR-5),(Reference example 15, PR-1), (Reference example 15, PR-2), (Referenceexample 15, PR-3), (Reference example 15, PR-4), (Reference example 15,PR-5), (Reference example 16, PR-1), (Reference example 16, PR-2),(Reference example 16, PR-3), (Reference example 16, PR-4), (Referenceexample 16, PR-5), (Reference example 17, PR-1), (Reference example 17,PR-2), (Reference example 17, PR-3), (Reference example 17, PR-4),(Reference example 17, PR-5), (Reference example 18, PR-1), (Referenceexample 18, PR-2), (Reference example 18, PR-3), (Reference example 18,PR-4), (Reference example 18, PR-5), (Reference example 19, PR-1),(Reference example 19, PR-2), (Reference example 19, PR-3), (Referenceexample 19, PR-4), (Reference example 19, PR-5), (Reference example 20,PR-1), (Reference example 20, PR-2), (Reference example 20, PR-3),(Reference example 20, PR-4), (Reference example 20, PR-5), (Referenceexample 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662, PR-1),(Reference example 662, PR-2), (Reference example 662, PR-3), (Referenceexample 662, PR-4), (Reference example 662, PR-5), (Reference example663, PR-1), (Reference example 663, PR-2), (Reference example 663,PR-3), (Reference example 663, PR-4), (Reference example 663, PR-5),(Reference example 664, PR-1), (Reference example 664, PR-2), (Referenceexample 664, PR-3), (Reference example 664, PR-4), (Reference example664, PR-5), (Reference example 665, PR-1), (Reference example 665,PR-2), (Reference example 665, PR-3), (Reference example 665, PR-4),(Reference example 665, PR-5)

For example, the above (Reference example 1, PR-1) means a compoundshown by the following structural formula:

As intermediate synthesis examples, methods for synthesizingintermediates useful for carrying out the present application are shownbelow.

Intermediate Synthesis Example 1

First Step

A solution of benzyl alcohol (1.00 g, 9.25 mmol) in THF (3 ml) was addedto a suspension of sodium tert-pentoxide (2.55 g, 23.2 mmol) in THF (4ml) at room temperature under nitrogen atmosphere, and the mixture wasstirred at 40° C. for 2 hours. This reaction solution was cooled in anice bath, and a THF (3 ml) solution of compound 1a (1.53 g, 10.2 mmol)was added dropwise at 0 to 10° C. After the reaction solution wasstirred at room temperature for 2 hours, 2N hydrochloric acid (15 ml)was added, followed by extraction with ethyl acetate two times. Thecombined extracts were washed sequentially with water, saturated sodiumbicarbonate water, water and aqueous saturated sodium chloride solution,and then dried with anhydrous sodium sulfate. The solvent was distilledoff, and the resulting oil was purified by silica gel columnchromatography (n-hexane-ethyl acetate 4:1, v/v) to obtain 1.89 g (yield92%) of compound 1b as an oil product.

¹H-NMR (CDCl₃) δ: 3.56 (2H, s), 3.71 (3H, s), 4.14 (2H, s), 4.59 (2H,s), 7.27-7.42 (5H, m).

Second Step

Compound 1b (1.80 g, 8.1 mmol) was dissolved in 1,4-dioxane (18 mL),N,N-dimethylformamide dimethyl acetal (1.45 g, 12.2 mmol) was added, andthe mixture was stirred at room temperature for 6 hours. The reactionsolution was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate1:4, v/v) to obtain 1.77 g (yield 79%) of compound 1e as an oil product.

¹H-NMR (CDCl₃) δ: 2.90 (3H, br), 3.25 (3H, br), 3.69 (3H, s), 4.45 (2H,s), 4.59 (2H, s), 7.24-7.40 (5H, m), 7.73 (s, 1H).

Third Step

Sodium tert-butoxide (2.55 g, 23.2 mmol), dimethyl oxalate (639 mg, 5.41mmol) and DMI (3 ml) were added to a three-neck flask under nitrogenatmosphere, and a DMI (2 ml) solution of compound 1e (0.50 g, 1.80 mmol)was added dropwise thereto at 25 to 30° C. After stirring at roomtemperature for 7 hours, 2N hydrochloric acid (10 ml) was added, and themixture was stirred at room temperature for 15 hours. The reactionsolution was extracted with ethyl acetate two times, and the combinedextracts were washed sequentially with water, saturated sodiumbicarbonate water, water and aqueous saturated sodium chloride solution,and then dried with anhydrous sodium sulfate. The solvent was distilledoff, and the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 2:1 to 1:1, v/v) to obtain 488 mg(yield 85%) of compound Id as a white solid.

¹H-NMR (CDCl₃) δ: 3.89 (3H, s), 3.93 (3H, s), 5.34 (2H, s), 7.32-7.40(3H, m), 7.45-7.49 (2H, m), 8.50 (1H, s).

Intermediate Synthesis Example 2

First Step

A DMI (3 ml) solution of benzyl alcohol (0.66 g, 6.1 mmol) was added toa DMI (4 ml) suspension of sodium tert-pentoxide (1.67 g, 15.2 mmol) atroom temperature under nitrogen atmosphere, and the mixture was stirredat 40° C. for 2 hours. This reaction solution was cooled in an ice bath,and a DMI (3 ml) solution of compound 2a (1.10 g, 6.68 mmol) was addeddropwise at 0 to 10° C. The reaction solution was stirred at 0 to 5° C.for 2 hours, and at room temperature for 3 hours, and 2N hydrochloricacid (15 ml) was added, followed by extraction with ethyl acetate twotimes. The combined extracts were washed sequentially with water,saturated sodium bicarbonate water, water and aqueous saturated sodiumchloride solution, and then dried with anhydrous sodium sulfate. Thesolvent was distilled off, and the resulting oil product was purified bysilica gel column chromatography (n-hexane-ethyl acetate 4:1, v/v) toobtain 1.29 g (yield 90%) of compound 2b as an oil product.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 3.54 (2H, s), 4.14 (2H, s),4.17 (2H, q, J=7.2 Hz), 4.59 (2H, s), 7.28-7.40 (5H, m).

Second Step

Compound 2b (9.73 g, 41.2 mmol) was dissolved in toluene (45 ml),N,N-dimethylformamide dimethyl acetal (7.36 g, 61.8 mmol) was added, andthe mixture was stirred at room temperature for 5 hours. Water was addedto the reaction solution, followed by extraction with ethyl acetate twotimes. The combined extracts were washed sequentially with water, andaqueous saturated sodium chloride solution, and then dried withanhydrous magnesium sulfate. The solvent was distilled off, and theresulting oil product was purified by silica gel column chromatography(n-hexane-ethyl acetate 1:1 to 3:7, v/v) to obtain 7.90 g (yield 66%) ofcompound 2c as an oil product.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 2.95 (3H, br), 3.22 (3H, br),4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.59 (2H, s), 7.22-7.40 (5H, m),7.73 (1H, s).

Third Step

Sodium tert-butoxide (495 mg, 5.15 mmol) and DMI (2 ml) were added to athree-neck flask under nitrogen atmosphere, and dimethyl oxalate (608mg, 5.15 mmol) and a DMI (3 ml) solution of compound 2c (0.50 g, 1.72mmol) were added dropwise thereto at 25 to 30° C. After stirring at roomtemperature for 4 hours, 2N hydrochloric acid (10 ml) was added, and themixture was stirred at room temperature for 15 hours. The reactionsolution was extracted with toluene two times, and the combined extractswere washed sequentially with water, saturated sodium bicarbonate water,water and aqueous saturated sodium chloride solution, and then driedwith anhydrous sodium sulfate. The solvent was distilled off, and theresulting residue was purified by silica gel column chromatography(n-hexane-ethyl acetate 2:1, v/v) to obtain 420 mg (yield 74%) ofcompound 2d as a white solid.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.2 Hz), 3.88 (3H, s), 4.39 (2H, q,J=7.2 Hz), 5.34 (2H, s), 7.30-7.41 (3H, m), 7.45-7.50 (2H, m), 8.48 (1H,s).

Intermediate Synthesis Example 3

First Step

N,N-dimethylformamide dimethyl acetal (4.9 ml, 36.5 mmol) was addeddropwise to compound 3a (5.0 g, 30.4 mmol) at 0° C. under cooling. Afterstirring at 0° C. for 1 hour, 100 ml of ethyl acetate was added to thereaction solution, followed by washing with 0.5N hydrochloric acid (50ml). The aqueous layer was separated, and extracted with ethyl acetate(50 ml). The organic layers were combined, washed sequentially withsaturated sodium bicarbonate water and aqueous saturated sodium chloridesolution, and then dried with anhydrous sodium sulfate. The solvent wasdistilled off, and the resulting residue was purified by silica gelcolumn chromatography (n-hexane-ethyl acetate 1:1 (v/v)→ethyl acetate)to obtain 4.49 g (yield 67%) of compound 3b as an oil product.

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.1 Hz), 2.90 (3H, brs), 3.29 (3H,brs), 4.23 (2H, q, J=7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).

Second Step

Lithium hexamethyldisilazide (1.0 M toluene solution, 49 ml, 49.0 mmol)was diluted with THF (44 ml), a THF (10 ml) solution of compound 3b(4.49 g, 20.4 mmol) was added dropwise thereto at −78° C. under cooling,and a THF (10 ml) solution of ethyl oxalyl chloride (3.35 g, 24.5 mmol)was added dropwise. After stirring at −78° C. for 2 hours, temperaturewas raised to 0° C. After 2N hydrochloric acid was added to the reactionsolution, and the mixture was stirred for 20 minutes, the solution wasextracted with ethyl acetate (200 ml×2), and the organic layer waswashed with saturated sodium bicarbonate water and aqueous saturatedsodium chloride solution and then dried with anhydrous sodium sulfate.The solvent was distilled off, and the resulting residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate 7:3→5:5→0:10(v/v)) to obtain 1.77 g (yield 31%) of compound 3c as a white solid.

¹H-NMR (CDCl₃) δ: 1.36-1.46 (6H, m), 4.35-4.52 (8H, m), 8.53 (1H, s).

Third Step

Aminoacetaldehyde dimethyl acetal (0.13 ml, 1.20 mmol) was added to anethanol (6 ml) solution of compound 3c (300 mg, 1.09 mmol) at 0° C., andthe mixture was stirred at 0° C. for 1 hour and 30 minutes, at roomtemperature for 18 hours and, then, at 60° C. for 4 hours. After thesolvent was distilled off from the reaction solvent under reducedpressure, the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 5:5→0:10 (v/v)) to obtain 252 mg(yield 64%) of compound 3d as an oil product.

¹H-NMR (CDCl₃) δ: 1.36-1.47 (6H, m), 3.42 (6H, s), 3.90 (2H, d, J=5.2Hz), 4.37 (3H, q, J=7.2 Hz), 4.50 (2H, q, J=7.2 Hz), 8.16 (1H, s).

Intermediate Synthesis Example 4

First Step

N,N-dimethylformamide dimethyl acetal (12.2 ml, 92.2 mmol) was addeddropwise to compound 4a (10.0 g, 76.8 mmol) at 0° C. under cooling.After stirring at 0° C. for 1 hour and 30 minutes and, then, at roomtemperature for 2 hours and 30 minutes, 100 ml of ethyl acetate wasadded to the reaction solution, and the solvent was distilled off. Theresulting residue was purified by silica gel column chromatography(n-hexane-ethyl acetate 5:5→0:10 (v/v)) to obtain 12.45 g (yield 88%) ofcompound 4b as an oil product.

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.1 Hz), 2.33 (3H, s), 3.04 (6H, brs),4.23 (2H, q, J=7.2 Hz), 7.68 (1H, s).

Second Step

Lithium hexamethyldisilazide (1.0 M toluene solution, 24 ml, 24.0 mmol)was diluted with THF (20 ml), a THF (5 ml) solution of compound 4b (1.85g, 10.0 mmol) was added dropwise thereto at −78° C. under cooling, and aTHF (5 ml) solution of ethyl oxalyl chloride (1.34 ml, 12.0 mmol) wasadded dropwise. After stirring at −78° C. for 2 hours, 2N-hydrochloricacid was added to the reaction solution, and the mixture was stirred atroom temperature for 20 minutes. The solution was extracted with ethylacetate, and the organic layer was washed sequentially with saturatedsodium bicarbonate water and aqueous saturated sodium chloride solution,and then dried with anhydrous sodium sulfate. The solvent was distilledoff, and the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 75:25→455:5 (v/v)) to obtain 1.03g (yield 43%) of compound 4c as a brown oil product.

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.4 Hz),4.33-4.47 (4H, m), 7.19 (1H, s), 8.54 (1H, s).

Third Step

Aminoacetaldehyde dimethyl acetal (0.34 ml, 3.11 mmol) was added to anethanol (6.8 ml) solution of compound 4c (680 mg, 2.83 mmol) at 0° C.,and the mixture was allowed to stand at room temperature for 16 hours.After the solvent was distilled off from the reaction solution underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (n-hexane-ethyl acetate 90:10 (v/v)) to obtain 875mg (yield 94%) of compound 4d as an oil product.

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 1.39 (3H, t, J=7.1 Hz), 3.40(6H, s), 4.33 (2H, d, J=4.7 Hz), 4.37 (4H, q, J=7.1 Hz), 4.49 (1H, t,J=4.7 Hz), 7.06 (1H, s), 8.17 (1H, s).

Fourth Step

N-bromosuccinimide (1.46 g, 8.18 mmol) was added to a DMF (10 ml)solution of compound 4d (2.68 g, 8.18 mmol), and the mixture was stirredat room temperature for 48 hours. After saturated sodium bicarbonatewater was added to the reaction solution, the solution was extractedwith ethyl acetate, and the organic layer was washed sequentially withwater and aqueous saturated sodium chloride solution, and then driedwith anhydrous sodium sulfate. The solvent was distilled off, and theresulting residue was purified by silica gel column chromatography(n-hexane-ethyl acetate 90:10 (v/v)) to obtain 2.83 g (yield 85%) ofcompound 4e as an oil product.

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 1.46 (3H, t, J=7.1 Hz), 3.42(6H, s), 3.88 (3H, d, J=5.0 Hz), 4.37 (3H, q, J=7.1 Hz), 4.51 (2H, q,J=7.1 Hz), 4.54 (2H, t, J=5.2 Hz), 8.17 (1H, s).

Intermediate Synthesis Example 5

First Step

Compound 5a (598 mg, 4.09 mmol) and N,N-dimethylformamide dimethylacetal (488 mg, 4.09 mmol) were dissolved in toluene (1 ml), and thesolution was stirred at room temperature for 11 hours. The solvent wasdistilled off from the reaction solution under reduced pressure, and theresulting residue (containing compound 5b) was used in Second stepwithout purification.

Second Step

Sodium tert-butoxide (400 mg, 4.16 mmol) was suspended in DMI (5 ml), aDMI (5 ml) solution of the crude product obtained in First step wasadded thereto, then, a THF (10 ml) solution of dimethyl oxalate (983 mg,8.32 mmol) was added dropwise, and the mixture was stirred at roomtemperature for 45 minutes. The reaction solution was poured into 2Nhydrochloric acid-methanol (20 ml), and the mixture was stirred at 0° C.for 20 minutes. Water was added, the solution was extracted with ethylacetate, and the organic layer was washed sequentially with water,saturated sodium bicarbonate water, and aqueous saturated sodiumchloride solution, and dried with anhydrous sodium sulfate. After thesolvent was distilled off, the resulting residue was purified by silicagel column chromatography to obtain 222 mg (yield: 22% from 5a) ofcompound 3C.

¹H-NMR (CDCl₃) δ: 3.91 (3H, s), 3.97 (3H, s), 4.05 (3H, s), 8.50 (1H,s).

Intermediate Synthesis Example 6

First Step

Lithium hexamethyldisilazide (1.0 M toluene solution, 12 ml, 12.0 mmol)was diluted with THF (11 ml), a THF (2 ml) solution of compound 6a (1.46g, 5.0 mmol) was added dropwise thereto at −78° C. under cooling, and aTHF (2 ml) solution of ethyl oxalyl chloride (0.67 ml, 6.0 mmol) wasadded dropwise. After stirring at −78° C. for 2 hours, ammonium acetate(500 mg) and acetic acid (10 ml) were added to the reaction solution,and the mixture was stirred at 65° C. for 1 hour and 30 minutes. Waterwas added to the reaction solution, the solvent was extracted with ethylacetate, and the organic layer was washed sequentially with water, andsaturated sodium bicarbonate water, and dried with anhydrous sodiumsulfate. The solvent was distilled off, and the resulting residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate55:45→45:55 (v/v)) to obtain 505.1 mg of compound 6b as a yellow solid.It was washed with isopropyl ether-hexane (1:2), and dried under reducedpressure to obtain 416.8 mg (yield 24%) of compound 6b as a yellowcrystal.

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 1.46 (3H, t, J=7.1 Hz), 4.40(2H, q, J=7.2 Hz), 4.50 (2H, q, J=7.1 Hz), 5.20 (2H, s), 7.33-7.41 (3H,m), 7.49-7.52 (2H, m), 8.76 (1H, s), 11.61 (1H, brs).

Second Step

Cesium carbonate (73.3 mg, 0.23 mmol) and bromoacetaldehyde dimethylacetal (38.0 mg, 0.23 mmol) were added to a DMF (1 ml) solution ofcompound 6b (51.8 mg, 0.15 mmol), and the mixture was stirred at roomtemperature overnight. Cesium carbonate (73.3 mg, 0.23 mmol) andbromoacetaldehyde dimethyl acetal (38.0 mg, 0.23 mmol) were furtheradded, and the mixture was further stirred at 100° C. for 20 minutes.After water was added to the reaction solution, the solution wasextracted with ethyl acetate, and the organic layer was washedsequentially with water and aqueous saturated sodium chloride solution,and dried with anhydrous sodium sulfate. The solvent was distilled off,and the resulting residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate 50:50→30:70 (v/v)) to obtain 35.3mg (yield 54%) of compound 6c as a colorless oil product.

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz), 3.39(6H, s), 3.91 (2H, d, J=5.0 Hz), 4.29 (2H, q, J=7.1 Hz), 4.40 (2H, q,J=7.2 Hz), 4.50 (1H, t, J=5.0 Hz), 5.30 (2H, s), 7.31-7.37 (3H, m),7.43-7.46 (2H, m), 8.12 (1H, s).

Intermediate Synthesis Example 7

First Step

Aminoacetaldehyde dimethyl acetal (7.80 mmol) was added to an ethanol (5ml) solution of compound 7a (900 mg, 2.60 mmol), and the mixture wasstirred at room temperature for 22 hours. Ethyl acetate (5 ml) and water(5 ml) were added to the reaction solution, followed by extraction withethyl acetate (5 ml). After the organic layer was washed with water (10ml), the solvent was distilled off, and the resulting residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate2:1) to obtain 0.37 g (yield 33%) of compound 7b as a colorless oilproduct.

¹H-NMR (CDCl₃) δ: 7.90 (1H, s), 7.45-7.43 (5H, m), 5.30 (2H, s), 4.51(1H, t, J=5.1 Hz), 4.40 (2H, q, J=7.1 Hz), 4.30 (2H, q, J=7.1 Hz), 3.91(2H, d, J=5.1 Hz), 3.46 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.26 (3H, t,J=7.1 Hz).

The compounds in connection with the present invention and/or the parentcompounds of the compounds in connection with the present invention areuseful for symptoms and/or diseases which are induced by influenzavirus. For example, they are useful for treating and/or preventing, orimproving symptoms of, cold-like symptoms accompanying fever, algor,headache, muscular pain, general malaise etc., airway inflammationsymptoms such as pharyngalgia, nasal secretion, nasal congestion, cough,sputum etc., gastrointestinal symptoms such as abdominal pain, vomitus,diarrhea etc. and, further, complications accompanying secondaryinfection such as acute encephalopathy and pneumonia.

Since the compounds in connection with the present invention are aprodrug and thus have advantages that oral absorbability is high, goodbioavailability is exhibited, good clearance is exhibited, and pulmonarytransitivity is high, they can be excellent medicaments.

Since the parent compounds of the compounds in connection with thepresent invention have the effects such as high inhibitory activity oncap structure-dependent endonuclease, and high selectivity due to avirus-specific enzyme, they can be medicaments having reduced sideeffects.

Further, since the compounds in connection with the present inventionand/or the parent compounds of the compounds in connection with thepresent invention also have advantages that metabolism stability ishigh, solubility is high, oral absorbability is high, goodbioavailability is exhibited, good clearance is exhibited, pulmonarytransitivity is high, a half life is long, a non-protein binding rate ishigh, hERG channel inhibition is low, CYP inhibition is low, CPE(CytoPathic Effect) inhibiting effect is recognized, and/or negativityis exhibited in a phototoxicity test, an Ames test and a gene toxicitytest, or toxicity such as liver damage is not caused. Therefore, thecompounds in connection with the present invention can be excellentmedicaments.

The compounds in connection with the present invention and/or the parentcompounds of the compounds in connection with the present invention canbe administered orally or parenterally. In the case of oraladministration, the present compounds can be also used as a normalpreparation, for example, as any dosage form of solid preparations suchas tablets, powders, granules, capsules etc.; solutions; oleaginoussuspensions; or liquid preparations such as syrups or elixirs etc. Inthe case of parenteral administration, the compounds in connection withthe present invention can be used as aqueous or oleaginous suspensioninjectables, or nose drops. Upon preparation of them, conventionalexcipients, binders, lubricants, aqueous solvents, oleaginous solvents,emulsifiers, suspending agents, preservatives, stabilizers etc. can bearbitrarily used. The pharmaceutical composition of the presentinvention can be produced by combining (for example, mixing) atherapeutically effective amount of the present compound withpharmaceutically acceptable carriers or diluents.

A dose of the compounds in connection with the present invention isdifferent depending on an administration method, an age, a weight andthe state of a patient, and a kind of a disease and, usually, in thecase of oral administration, about 0.05 mg to 3000 mg, preferably about0.1 mg to 1000 mg for adult per day may be administered, if necessary,by division. In addition, in the case of parenteral administration,about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg for adultper day is administered.

Test Example 1: Measurement of Cap-Dependant Endonuclease (CEN)Inhibitory Activity 1) Preparation of Substrate

30merRNA(5′-pp-[m2′-O]GAA UAU(-Cy3) GCA UCA CUA GUA AGC UUU GCUCUA-BHQ2-3′: manufactured by Japan Bio Services Co., LTD.) in which G ata 5′ end is diphosphate-modified, a hydroxy group at 2′ position ismethoxylation-modified, U sixth from a 5′ end is labelled with Cy3, anda 3′ end is labelled with BHQ2 was purchased, and a cap structure wasadded using ScriptCap system manufactured by EPICENTRE (a product wasm7G [5′]-ppp-[5′] [m2′-O]GAA UAU(-Cy3) GCA UCA CUA GUA AGC UUU GCUCUA(-BHQ2)-3′). This was separated and purified by denaturedpolyacrylamide gel electrophoresis, and used as a substrate.

2) Preparation of Enzyme

RNP was prepared from a virus particle using standard method (ReferenceDocument: VIROLOGY (1976) 73, p 327-338 OLGA M. ROCHOVANSKY).Specifically, A/WSN/33 virus (1×10³ PFU/mL, 200 μL) was inoculated in a10 days old embryonated chicken egg. After incubation at 37° C. for 2days, the allantoic fluid of the chicken egg was recovered. A virusparticle was purified by ultracentrifugation using 20% sucrose,solubilized using TritonX-100 and lysolecithin, and an RNP fraction(50-70% glycerol fraction) was collected by ultracentrifugation using a30-70% glycerol density gradient, and was used as an enzyme solution(containing approximately 1 nM PB1-PB2-PA complex).

3) Enzymatic Reaction

An enzymatic reaction solution (2.5 μL) (composition: 53 mMTris-hydrochloride (pH 7.8), 1 mM MgCl₂, 1.25 mM dithiothreitol, 80 mMNaCl, 12.5% glycerol, enzyme solution 0.15 μL) was dispensed into a384-well plate made of polypropylene. Then, 0.5 μL of a test compoundsolution which had been serially diluted with dimethyl sulfoxide (DMSO)was added to the plate. As a positive control (PC) or a negative control(NC), 0.5 μL of DMSO was added to the plate respectively. Each plate wasmixed well. Then, 2 μL of a substrate solution (1.4 nM substrate RNA,0.05% Tween20) was added to initiate a reaction. After room temperatureincubation for 60 minutes, 1 μL of the reaction solution was collectedand added to 10 μL of a Hi-Di formamide solution (containing GeneScan120 Liz Size Standard as a sizing marker: manufactured by AppliedBiosystems (ABI)) in order to stop the reaction. For NC, the reactionwas stopped in advance by adding EDTA (4.5 mM) before initiation of thereaction (all concentrations described above are final concentrations).

3) Measurement of Inhibition Ratio (IC₅₀ Value)

The solution for which the reaction was stopped was heated at 85° C. for5 minutes, rapidly cooled on ice for 2 minutes, and analyzed with an ABIPRIZM 3730 genetic analyzer. A peak of the cap-dependent endonucleaseproduct was quantitated by analysis software ABI Genemapper, a CENreaction inhibition ratio (%) of a test compound was obtained by settingfluorescent intensities of PC and NC to be 0% inhibition and 100%inhibition, respectively, an IC₅₀ value was obtained using curve fittingsoftware (XLfit2.0: Model 205 (manufactured by IDBS) etc.). The IC₅₀values of test substances being a parent compound, are shown in Tables22 to 34.

Test Example 2: CYP Inhibition Test

Using commercially available pooled human liver microsomes, andemploying, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2),tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation(CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadinehydroxylation (CYP3A4) as typical substrate metabolism reactions ofhuman main five CYP enzyme forms (CYPIA2, 2C9, 2C19, 2D6, 3A4), aninhibitory degree of each metabolite production amount by a testcompound was assessed.

The reaction conditions were as follows: substrate, 0.5 μmol/Lethoxyresorufin (CYPIA2), 100 μmol/L tolbutamide (CYP2C9), 50 mol/LS-mephenytoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/Lterfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature,37° C.; enzyme, pooled human liver microsomes 0.2 mg protein/mL; testdrug concentration, 1, 5, 10, 20 μmol/L (four points).

Each five kinds of substrates, human liver microsomes, or a test drug in50 mM Hepes buffer as a reaction solution was added to a 96-well plateat the composition as described above, NADPH, as a cofactor was added toinitiate metabolism reactions as markers and, after the reaction at 37°C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was addedto stop the reaction. After the centrifugation at 3000 rpm for 15minutes, resorufin (CYP1A2 metabolite) in the centrifugal supernatantwas quantified by a fluorescent multilabel counter and tolubtamidehydroxide (CYP2C9 metabolite), mephenytoin 4′ hydroxide (CYP2C19metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol(CYP3A4 metabolite) were quantified by LC/MS/MS.

Addition of only DMSO being a solvent dissolving a drug to a reactionsystem was adopted as a control (100%), remaining activity (%) wascalculated at each concentration of a test drug added as the solutionand IC₅₀ was calculated by reverse presumption by a logistic model usinga concentration and an inhibition rate.

Test Example 3: Solubility Test

The solubility of each compound was determined under 1% DMSO additionconditions. A 10 mM solution of the compound was prepared with DMSO, and6 μL of the compound solution was added to 594 μL of an artificialintestinal juice (water and 118 mL of 0.2 mol/L NaOH reagent were addedto 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent to reach1000 mL) with pH of 6.8. The mixture was left standing for 16 hours at25° C., and the mixture was vacuum-filtered. The filtrate was two-folddiluted with methanol/water=1/1, and the compound concentration in thefiltrate was measured with HPLC or LC/MS/MS by the absolute calibrationmethod.

Test Example 4: Metabolism Stability Test

A reaction was performed (oxidative reaction) at 37° C. for 0 minute or30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50mmol/L tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/Lmagnesium chloride) containing 0.5 mg protein/mL of human livermicrosomes. After the reaction, 50 μL of the reaction solution was addedto 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at3000 rpm for 15 minutes. The test compound in the supernatant wasquantified by LC/MS/MS, and a remaining amount of the test compoundafter the reaction was calculated, letting a compound amount at 0 minutereaction time to be 100%. Hydrolysis reaction was performed in theabsence of NADPH and glucuronidation reaction was performed in thepresence of 5 mM UDP-glucuronic acid in place of NADPH, followed bysimilar operations.

Test Example 5: hERG Test

For the purpose of assessing risk of an electrocardiogram QT intervalprolongation, effects on delayed rectifier K⁺ current (I_(Kr)), whichplays an important role in the ventricular repolarization process, wasstudied using HEK293 cells expressing human ether-a-go-go related gene(hERG) channel.

After a cell was retained at a membrane potential of −80 mV by wholecell patch clamp method using an automated patch clamp system(PatchXpress 7000A, Axon Instruments Inc.), I_(Kr) induced bydepolarization pulse stimulation at +50 mV for 2 seconds and, further,repolarization pulse stimulation at −50 mV for 2 seconds was recorded.After the generated current was stabilized, extracellular solution(NaCl: 137 mmol/L, KCl: 4 mmol/L, CaCl₂.2H₂O: 1.8 mmol/L, MgCl₂.6H₂O: 1mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4) in which the test substance hadbeen dissolved at an objective concentration was applied to the cellunder the room temperature condition for 10 minutes. From the resultingI_(Kr), an absolute value of the tail peak current was measured based onthe current value at the resting membrane potential using an analysissoftware (DataXpress ver.1, Molecular Devices Corporation). Further, theinhibition rate relative to the tail peak current before application ofthe test substance was calculated, and compared with the vehicle-appliedgroup (0.1% dimethyl sulfoxide solution) to assess influence of the testsubstance on I_(Kr).

Test Example 6: CPE Inhibitory Effect Confirming Assay <Material>

2% FCS E-MEM (prepared by adding kanamycin and FCS to MEM (MinimumEssential Medium) (Invitrogen))

0.5% BSA E-MEM (prepared by adding kanamycin and BSA to MEM (MinimumEssential Medium) (Invitrogen))

HBSS (Hanks' Balanced Salt Solution)

MDBK cell

Cells were adjusted to the appropriate cell number (3×10⁵/mL) with 2%FCS E-MEM.

MDCK cell

After washing with HBSS two times, cells were adjusted to theappropriate cell number (5×10⁵/mL) with 0.5% BSA E-MEM.

Trypsin solution

Trypsin from porcine pancreas (SIGMA) was dissolved in PBS(-), andfiltrated with a 0.45 μm filter.

EnVision (PerkinElmer)

WST-8 Kit (Kishida Chemical Co., Ltd.)

10% SDS solution

<Operation Procedure>

Dilution and Dispensation of Test Sample

As a culture medium, 2% FCS E-MEM was used at the use of MDBK cells, and0.5% BSA E-MEM was used at the use of MDCK cells. Hereinafter, fordiluting virus, cells and a test sample, the same culture medium wasused.

A test sample was diluted with a culture medium to an appropriateconcentration in advance, and then 2 to 5-fold serial dilution on a 96well plate (50 μL/well) was prepared. Two plates, one for measuringanti-Flu activity and the another for measuring cytotoxity, wereprepared. Each assay was performed triplicate for each drug.

At the use of MDCK cells, Trypsin was added to the cells to be a finalconcentration of 3 pg/mL only for measuring anti-Flu activity.

Dilution and Dispensation of Influenza Virus

An influenza virus was diluted with a culture medium to an appropriateconcentration in advance, and each 50 μL/well was dispensed on a 96-wellplate containing a test substance. Each 50 μL/well of a culture mediumwas dispensed on a plate containing a test substance for measuringcytotoxity.

Dilution and Dispensation of Cell

Each 100 μL/well of cells which had been adjusted to the appropriatecell number was dispensed on a 96 well plate containing a test sample.This was mixed with a plate mixer, and incubated in a CO2 incubator for3 days for measuring anti-Flu activity and measuring cytotoxity.

Dispensation of WST-8

The cells in the 96-well plate which had been incubated for 3 days wasobserved visually under a microscope, and appearance of the cells, thepresence or absence of a crystal of test substance were checked. Thesupernatant was removed so that the cells were not absorbed from theplate.

WST-8 Kit was diluted 10-fold with a culture medium, and each 100 μL wasdispensed into each well. After mixing with a plate mixer, cells wereincubated in a CO2 incubator for 1 to 3 hours. After incubation,regarding the plate for measuring anti-Flu activity, each 10 μL/well ofa 10% SDS solution was dispensed in order to inactivate a virus.

Measurement of Absorbance

After the 96-well plate was mixed, absorbance was measured with EnVisionat two wavelengths of 450 nm/620 nm.

<Calculation of Each Measurement Item Value>

The value was calculated using Microsoft Excel or a program having theequivalent calculation and processing ability, based on the followingcalculation equation.

Calculation of Effective Inhibition Concentration to Achieve 50%Influenza Infected Cell Death (EC50)

EC50=10{circumflex over ( )}Z

Z=(50%−High %)/(High %−Low %)×{log(High conc.)−log(Low conc.)}+log(Highconc.)

For test substances (compounds of Reference examples) being a parentcompound, measurement results of Test Example 1 and Test Example 6 areshown in Tables 22 to 34.

TABLE 22 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 2 0.048 0.29314 0.043 0.313 16 0.065 0.632 26 0.108 0.547 37 0.101 0.318 43 0.0781.410 48 0.087 10.90 56 0.358 3.860 62 0.110 1.680 63 0.170 2.000 940.096 1.470 99 0.341 2.000 108 0.037 0.019 128 0.063 0.416 138 0.1660.100 139 0.189 0.741 143 0.224 0.333 150 0.193 0.553 175 0.132 0.102178 0.061 0.075

TABLE 23 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 181 0.0490.349 182 0.099 0.562 183 0.074 2.370 184 0.055 0.403 185 0.132 1.920186 0.085 0.159 187 0.085 0.282 190 0.143 2.640 191 0.238 2.820 1990.236 2.720 204 0.299 2.360 224 0.276 0.119 225 0.283 0.663 228 0.2430.141 230 0.282 0.525 233 0.228 2.240 238 0.101 0.440 240 0.037 0.048241 0.197 0.063 242 0.114 0.059 243 0.076 0.020 244 0.249 0.108 2460.082 0.026 247 0.282 2.260 248 0.103 0.489 249 0.151 1.890 250 0.1130.476 251 0.058 0.157 252 0.107 0.454 253 0.235 0.280 254 0.135 0.564255 0.052 0.319 256 0.038 0.400

TABLE 24 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 257 0.0410.055 258 0.042 0.028 259 0.066 0.026 260 0.091 0.065 261 0.058 0.047262 0.032 0.038 263 0.085 0.075 264 0.064 0.128 265 0.172 0.036 2660.043 0.085 267 0.029 0.063 268 0.018 0.074 269 0.073 0.417 270 0.0580.129 271 0.073 0.102 272 0.082 0.030 273 0.016 0.084 274 0.038 0.016274 0.157 0.056 276 0.053 0.089 277 0.039 0.071 278 0.205 0.074 2790.056 0.119 280 0.068 0.145 281 0.026 0.018 282 0.036 0.029 283 0.0280.021 284 0.042 0.019 285 0.044 0.017 286 0.161 0.121 287 0.154 0.268288 0.299 0.085 289 0.031 0.419

TABLE 25 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 290 0.0670.492 292 0.155 2.230 293 0.290 0.437 294 0.035 0.018 295 0.052 0.334296 0.130 0.397 297 0.045 0.033 298 0.044 0.012 299 0.050 0.015 3000.058 0.021 301 0.062 0.017 302 0.035 0.014 304 0.018 0.015 305 0.0590.103 306 0.076 0.021 307 0.052 0.095 308 0.072 0.019 309 0.040 0.013310 0.108 0.522 311 0.040 0.026 312 0.019 0.029 313 0.189 0.050 3140.149 0.026 315 0.057 0.115 316 0.069 0.083 317 0.048 0.017 318 0.1300.015 320 0.045 0.011 321 0.019 0.019 322 0.113 0.028 323 0.077 0.019324 0.107 0.035 325 0.032 0.025

TABLE 26 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 326 0.0430.005 327 0.092 0.024 328 0.029 0.168 329 0.058 0.023 330 0.026 0.019331 0.045 0.335 332 0.048 0.020 333 0.021 0.425 334 0.075 0.032 3350.019 0.016 336 0.051 0.070 337 0.058 0.028 338 0.074 0.085 339 0.1830.040 340 0.101 0.027 341 0.016 0.027 342 0.099 0.026 343 0.122 0.018344 0.050 0.009 345 0.097 0.008 346 0.028 0.018 347 0.014 0.017 3480.054 0.080 349 0.053 0.075 351 0.091 0.019 352 0.067 0.020 354 0.0250.083 355 0.040 0.075 356 0.066 0.020 357 0.138 0.386 358 0.051 0.069359 0.037 0.080 360 0.042 0.087

TABLE 27 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 361 0.0390.145 362 0.084 0.067 363 0.058 0.067 364 0.112 0.515 365 0.041 2.250366 0.090 0.838 368 0.140 0.470 369 0.294 0.434 370 0.113 0.061 3710.161 0.074 372 0.164 0.146 373 0.065 0.050 374 0.137 0.154 375 0.0370.073 376 0.063 0.092 377 0.024 0.022 378 0.047 0.022 380 0.123 0.018381 0.200 0.034 382 0.032 0.094 384 0.153 0.293 386 0.075 0.096 3870.300 1.150 388 0.133 0.063 390 0.095 0.029 391 0.264 0.071 392 0.1530.025 394 0.087 0.064 395 0.043 0.089 396 0.056 0.060 397 0.055 0.077398 0.034 0.118 399 0.105 0.061

TABLE 28 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 400 0.0670.079 401 0.089 0.133 402 0.085 0.081 403 0.090 0.070 404 0.084 0.063405 0.074 0.051 406 0.119 0.022 407 0.035 0.017 408 0.135 0.061 4090.093 0.029 410 0.265 0.014 411 0.046 0.014 412 0.292 0.203 413 0.0500.005 414 1.890 0.131 415 0.285 0.022 416 0.112 0.019 417 0.030 0.003418 0.121 0.072 419 0.124 0.019 420 0.058 0.021 423 0.280 0.019 4250.183 0.047 429 0.016 0.004 430 0.168 0.029 431 0.097 0.011 432 0.1550.062 433 0.014 0.017 441 0.044 0.005 443 0.166 0.004 444 0.066 0.003445 0.013 0.004 446 0.007 0.011

TABLE 29 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 447 0.0960.018 448 0.039 0.008 449 0.062 0.021 450 0.023 0.014 452 0.177 0.016453 0.186 0.049 454 0.012 0.004 455 0.025 0.071 456 0.032 0.004 4570.242 0.014 458 0.048 0.014 459 0.287 0.048 460 0.085 0.009 461 0.2550.074 462 0.069 0.011 463 0.012 0.005 464 0.024 0.014 469 0.016 0.004470 0.008 0.003 475 0.164 0.441 476 0.031 0.014 478 0.088 0.129 4790.117 0.064 480 0.151 0.084 481 0.114 0.086 482 0.103 0.031 483 0.1010.027 485 0.221 0.424 486 0.140 0.072 487 0.091 0.026 488 0.151 0.027489 0.133 0.014 490 0.212 0.468

TABLE 30 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 491 0.0690.099 492 0.121 0.160 493 0.112 0.101 495 0.277 0.310 496 0.170 0.177497 0.215 0.511 498 0.161 0.351 502 0.042 0.142 506 0.247 1.620 5070.063 0.197 508 0.036 0.056 509 0.015 0.014 511 0.175 0.015 514 0.0490.018 515 0.197 0.019 516 0.039 0.017 518 0.049 0.024 520 0.212 0.017521 0.191 0.015 522 0.039 0.014 523 0.035 0.014 524 0.057 0.026 5250.141 0.090 526 0.044 0.019 527 0.127 0.088 532 0.098 0.075 533 0.0650.391 534 0.165 1.200 536 0.071 0.027 537 0.152 0.022 538 0.196 0.030544 0.168 0.051 546 0.202 0.124

TABLE 31 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 547 0.0320.027 548 0.086 0.038 549 0.076 2.100 550 0.042 0.042 551 0.041 0.107552 0.230 0.085 553 0.028 0.030 554 0.065 0.465 555 0.023 0.012 5560.023 0.412 557 0.281 2.470 558 0.114 0.541 560 0.027 0.173 561 0.0730.008 562 0.022 0.062 563 0.049 0.464 564 0.088 0.136 565 0.154 0.726568 0.264 2.810 569 0.138 1.010 570 0.081 2.050 571 0.065 0.320 5730.055 0.158 574 0.165 0.442 575 0.058 0.087 576 0.063 0.027 577 0.2330.337 581 0.083 0.480

TABLE 32 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 592 0.0290.012 594 0.011 0.004 597 0.339 0.049 598 0.016 0.005 599 0.025 0.008600 0.059 0.036 601 0.025 0.008 602 0.005 0.004 603 0.037 0.015 6090.053 0.025 611 0.055 0.043 612 0.055 0.013 613 0.173 0.018 617 0.0530.017 618 0.029 0.018 619 0.005 0.006 621 0.006 0.002 622 0.089 0.012623 0.021 0.003 624 0.065 0.057 628 0.043 0.013 629 0.089 0.064 6310.075 0.041 632 0.132 0.038

TABLE 33 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 633 0.0530.022 634 0.103 0.017 636 0.074 0.015 638 0.130 0.021 639 0.055 0.017640 0.057 0.006 641 0.046 0.023 642 0.256 0.094 643 0.163 0.132 6440.238 0.060 645 0.105 0.016 648 0.132 0.059 649 0.182 0.051 650 0.2190.103 651 0.056 0.013 652 0.330 0.079 654 0.008 0.001 656 0.070 0.019658 0.053 0.019 660 0.036 0.011 661 0.135 0.014 662 0.316 0.022 6630.031 0.018 665 0.018 0.005

TABLE 34 Reference CEN IC₅₀ CPE EC₅₀ example No. (μM) (μM) 666 0.003360.00391 668 0.0126 0.00384 682 0.0197 0.0035 686 0.0151 0.00786 6910.00367 0.00405 692 0.0369 0.00964 704 0.0111 0.0035 706 0.0186 0.00719707 0.0402 0.00305 708 0.0465 0.00849 709 0.0343 0.00709 710 0.02060.00981 711 0.00557 0.00428 712 0.0164 0.00645 716 0.00554 0.0056 7190.0026 0.00836 720 0.0191 0.00624 721 0.00696 0.00395 722 0.0192 0.00378724 0.00507 0.00633 726 0.00374 0.00393 728 0.0747 0.00432 730 0.002520.000799 731 0.00576 0.00208 741 0.021 0.00351 748 0.0242 0.00914 7520.0142 0.00312 753 0.109 0.0185 762 0.0315 0.0059 768 0.0153 0.00364 7710.00589 0.00405 772 0.00522 0.00368

Based on the above results, the parent compounds exhibit highcap-dependent endonuclease (CEN) inhibitory activity and/or high CPEinhibitory effect and thus can be a useful agent for treatment and/orprevention of symptom and/or disease induced by infection with influenzavirus.

Test Example 7: Influenza Virus-Infected Mouse Lethality Inhibitory Test<Mouse>

BALB/cAnNCrlCrlj (female, 5-week-old; CHARLES RIVER LABORATORIES JAPAN,INC.) was purchased, and 6- to 7-week-old mice were used in the test.

<Preparation of Virus Solution>

A/WS/33, A/Victoria/3/75 or B/Maryland/1/59 (ATCC) was passaged in mouselung to make a mouse-acclimatized virus. A freezing-storedmouse-acclimatized virus solution was rapidly thawed, and diluted withDPBS to an infectivity titer to be used (in the case ofA/WS/33:800-4000TCID₅₀/mouse, in the case ofA/Victoria/3/75: 750 TCIDs/mouse, inthe case of B/Maryland/1/59: 100 TCIDso/mouse).

<Infection>

Under anesthesia with ketamine.xylazine mixture, 100 ul of the preparedvirus solution was nasally inoculated to directly infect mouse lung.

<Preparation of Test Sample>

A test sample was suspended in a 0.5% methylcellulose solution to asuitable concentration.

<Administration of Test Sample to Infected Mouse>

A suitably diluted test sample was orally administered at 200 ul to amouse immediately after virus infection or after the elapse of a certainperiod of time.

<Drug Efficacy Assessment>

The mouse was reared for 14 days after virus infection, and a necessarydose per day for 50% lethality inhibition, ED₅₀ (mg/kg/day), a lethalityinhibition rate at a maximum dose (% survival), or days during which themouse survives 50% as compared with a control at a maximum dose (50%life extension days) was calculated. Alternatively, the amount of virusin the lung for several days after virus infection was measured, andcompared with the amount of virus of control to evaluate virusinhibitory effect.

<Euthanasia>

The mouse after completion of the test was euthanized by carbon dioxideor halothane excessive administration.

<Result>

The ED₅₀ values of single dose are shown.

Number of compound of Reference example 413: 12.3

Number of compound of Example 20: 4.4

Based on the above results, it was revealed that compound of Example 20obtained by converting compound of Reference example 413 being a parentcompound into a prodrug exhibits lethality inhibitory effect at lowerconcentration.

Test Example 8: BA Test

Experimental material and method for studying oral absorbability

(1) Animal to be used: A mouse or rat was used.

(2) Rearing conditions: Mouse and rat ingested a solid feed andsterilized tap water ad-libitum.

(3) Dose and setting of grouping: A predetermined dose was administeredorally or intravenously. A group was set as follows. (a dose varied forevery compound)

Oral administration 1 to 30 mg/kg (n=2 to 3)

Intravenous administration 0.5 to 10 mg/kg (n=2 to 3)

(4) Preparation of administration solution: For oral administration, asolution or suspension was administered. For intravenous administration,a compound which was solubilized was administered.

(5) Administration method: For oral administration, the administrationsolution was forcibly administered to the stomach by oral sonde. Forintravenous administration, the administration solution was administeredwith a syringe equipped with an injection needle through a tail vein.

(6) Assessment item: Blood was collected with time, and a plasma drugconcentration was measured using LC/MS/MS.

(7) Statistical analysis: Regarding plasma concentration transition, anarea under a plasma concentration-time curve (AUC) was calculated usinga non-linear minimum square method program WinNonlin (registeredtrademark), and bioavailability (BA) was calculated from AUC of anoral-administered group and an intervenous-administered group.

<Result>

The measurement results measured using a rat are shown in the followingTable 35.

TABLE 35 Reference example No Parent compound Example No. Prodrug(Parent compound) BA (%) (Prodrug) BA (%) 301 2.3 114 6.8 301 2.3 20413.0 413 4.3 20 13.2 429 13.3 137 19.8 429 13.3 146 30.5 445 12.1 11723.3 445 12.1 155 26.9 445 12.1 209 18.6 592 4.2 100 10.7 592 4.2 14117.9 592 4.2 160 15.8 594 5.0 104 14.8 594 5.0 116 21.3 594 5.0 142 10.3594 5.0 156 17.8

Based on the above results, the prodrug had improved bioavailabilityother than the parent compound.

Therefore, the compound of the present invention has excellent oralabsorbability and can be a useful agent for treatment and/or preventionof symptom and/or disease induced by infection with influenza virus.

FIGS. 1 to 4 show a result of determining changes in the plasmaconcentration of Reference example 301, for compounds of Examples 114and 204 prepared by converting compound of Reference example 301 being aparent compound into a prodrug, after oral administration to rat undernon-fasting conditions.

BA after oral administrating Examples 114 and 204 was 6.8% and 13.0%,respectively. Improvement of bioavailability was found when compared tothe case of orally administrating compound of Reference example 301being a parent compound (BA=2.3%). The Tmax values of both compoundswere 1 hr or less, and it was shown that oral absorbability was high. Inaddition, in compounds of Examples 114 and 204, the concentration in allplasma samples was a determination limit or less.

Based on the above test results, it was revealed that the compound ofExample converted into a prodrug was absorbed into the body after oraladministration, and rapidly converted into a parent compound in theblood. Therefore, the compound of the present invention can be a usefulagent for treatment and/or prevention of symptom and/or disease inducedby infection with influenza virus.

Formulation Example 1

A granule containing the following ingredients is manufactured.

Ingredients A compound represented by formula (I)  10 mg Lactose 700 mgCornstarch 274 mg HPC-L  16 mg 1000 mg 

A compound represented by formula (I) and lactose are passed through a60 mesh sieve. Cornstarch is passed through a 120 mesh sieve. These aremixed with a V-type blender. To the mixed powder is added an aqueousHPC-L (low viscosity hydroxypropylcellulose) solution, and the mixtureis kneaded together, granulated (extrusion granulation, pore diameter0.5-1 mm), and dried. The obtained dried granule is passed through avibrating sieve (12/60 mesh) to obtain a granule.

Formulation Example 2

A granule for encapsulation containing the following ingredients ismanufactured.

Ingredients A compound represented by formula (I) 15 mg Lactose 90 mgCornstarch 42 mg HPC-L  3 mg 150 mg 

A compound represented by formula (I) and lactose are passed through a60 mesh sieve. Cornstarch is passed through a 120 mesh sieve. These aremixed, a HPC-L solution is added to the mixed powder, then the mixtureis kneaded together, granulated, and dried. The obtained dried granuleis trimmed, and then 150 mg thereof is filled into a No. 4 hard gelatincapsule.

Formulation Example 3

A tablet containing the following ingredients is manufactured.

Ingredients A compound represented by formula (I) 10 mg Lactose 90 mgmicrocrystalline cellulose 30 mg CMC-Na 15 mg Magnesium stearate  5 mg150 mg 

A compound represented by formula (I), lactose, microcrystallinecellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passedthrough a 60 mesh sieve and mixed. Magnesium stearate is added to themixed powder to obtain a mixed powder for tablet. The mixed powder iscompressed directly to obtain a 150 mg tablet.

Formulation Example 4

The following ingredients were mixed under heat, and then sterilized toobtain an injectable solution.

Ingredients A compound shown by formula (I) 3 mg Nonionic surfactant 15mg Purified water for injection 1 ml

INDUSTRIAL APPLICABILITY

The compound of the present invention has cap-dependent endonuclease(CEN) inhibitory activity after absorption into the body. The compoundof the present invention can be a useful agent for treatment and/orprevention of symptom and/or disease induced by infection with influenzavirus.

1-24. (canceled)
 25. Use of Reference example 25 for treating a disease.